Neuroglia doi: 10.3390/neuroglia7030032

Authors: Alan Pereira da Costa Amanda Sotero Martins Leticia Viana Mendes Ana Clara da Silva Lopes Kethely Lima Marques Raman Alves dos Reis Marta Cristina da Cunha-Rodrigues Gustavo Casimiro Lopes Penha Cristina Barradas

Background/objectives: Perinatal hypoxia–ischemia (HI) is a major cause of brain injury and is associated with long-term neurological impairments, including white matter injury, astrogliosis, microgliosis, and hypomyelination. Maternal exercise has emerged as a potential non-pharmacological strategy to improve fetal development and increase resilience to prenatal insults. This study investigated whether maternal exercise during pregnancy protects against neuroglial alterations in the corpus callosum of offspring subjected to prenatal HI. Methods: Adult female Wistar rats were assigned to sedentary or exercise groups. The exercise protocol consisted of daily swimming sessions with progressive durations (3–30 min/day) over 10 days. Blood glucose levels and oxidative stress markers (GSH, TBARS, and DPPH) were evaluated to characterize the physiological effects of the protocol. Prenatal HI was induced on gestational day 18 by transient occlusion of the uterine arteries for 45 min, whereas sham-operated dams underwent identical surgical procedures without arterial occlusion. Offspring were euthanized on postnatal days (P) 16 and 23, and brain sections were processed for immunohistochemistry using antibodies against glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). Images were quantitatively analyzed using Image-Pro Plus, and statistical analyses were performed using SPSS software. Results: The exercise protocol did not show oxidative stress, hypoglycemia, or exhaustion. Female offspring from HI group exhibited astrogliosis at P16, which persisted until P23; however, maternal exercise prevented this response at P23. No changes in MBP immunoreactivity were detected in females. Male offspring did not develop astrogliosis but displayed hypomyelination at P23, which was prevented by maternal exercise. Conclusions: These findings demonstrate that maternal exercise during pregnancy attenuates sex-dependent neuroglial alterations induced by prenatal HI, supporting its potential as a preventive strategy to reduce white matter injury and improve neurodevelopmental outcomes.

Neuroglia doi: 10.3390/neuroglia7030031

Authors: Abba Musa Abdullahi Usama Ishaq Abdulrazak Ahmad Zubairu Abdurrahman

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy, where seizures remain uncontrolled despite appropriate trials of at least two antiseizure medications (ASMs). Neuroinflammation, specifically chronic microglial activation, plays an important role in epileptogenesis, seizure perpetuation, and pharmacoresistance. Traditionally, antiseizure medications (ASMs) target neuronal excitability through modulation of ion channels and neurotransmitter systems; however, several ASMs, including sodium valproate and lamotrigine, have demonstrated anti-inflammatory and microglia-modulating properties beyond their conventional antiseizure mechanisms. Rational polytherapy involving combinations of ASMs with complementary mechanisms and anti-neuroinflammatory effects may provide enhanced seizure control while minimizing adverse effects. Among available combinations, sodium valproate and lamotrigine have consistently been regarded as one of the few combinations demonstrating potential pharmacodynamic synergism. Although several clinical studies have evaluated this combination in pediatric DRE, the overall evidence has not been quantitatively synthesized. Objectives: To systematically evaluate the efficacy and safety of rational polytherapy with sodium valproate plus lamotrigine in children with drug-resistant epilepsy. Methods: Electronic databases, including PubMed, Medline, Scopus, Embase, Web of Science, Google Scholar, PubMed Central, ScienceDirect, Cochrane Library, and clinicaltrials.gov, were systematically searched. Studies involving pediatric patients aged 18 years or less with DRE receiving polytherapy regimens containing sodium valproate plus lamotrigine were included. Primary outcomes were total treatment effect defined as ≥50% seizure reduction and seizure freedom. Secondary outcomes included changes in seizure frequency, adverse events, treatment discontinuation, and serious adverse events. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle–Ottawa Scale. Meta-analyses were performed using random-effects models. Results: A total of 7 studies met the eligibility criteria. The pooled proportion of patients achieving an overall treatment response was 65.3% (95% CI 51.8–78.8%), with high heterogeneity (I2 = 63.4%, p = 0.027). Rational polytherapy with sodium valproate plus lamotrigine combination provided preliminary comparative evidence of higher responder rates in a single comparative trial, requiring confirmation in larger randomized trials. Overall, sodium valproate plus lamotrigine was well tolerated, and most reported adverse events were mild to moderate in severity. The pooled adverse event rate was 18.1% (95% CI 8.3–28.0%), with high heterogeneity (I2 = 64.3%, p = 0.024). Conclusions: Rational polytherapy with sodium valproate plus lamotrigine that have both complementary antiseizure and immunomodulatory mechanisms appears to represent an effective and generally well-tolerated therapeutic strategy for pediatric drug-resistant epilepsy. However, the basis of this conclusion is derived mainly from observational studies, requiring confirmation in larger randomized trials. This systematic review provides quantitative evidence supporting its clinical use while highlighting the need for larger prospective comparative studies to strengthen the evidence base.

Neuroglia doi: 10.3390/neuroglia7030030

Authors: Karen Gillian Luis-Hernández Luis Beltrán-Parrazal Consuelo Morgado-Valle María Leonor López-Meraz Luis I. García Donaji Chi-Castañeda

The Tau protein is traditionally recognized for stabilizing axonal microtubules in neurons. However, emerging evidence indicates that astrocytes also show basal expression of the microtubule-associated protein Tau (MAPT) gene, with potential implications for central nervous system (CNS) homeostasis. Under physiological conditions, astrocytes support functions essential to CNS integrity, including metabolic support, neurotransmitter uptake, blood–brain barrier maintenance, and immune surveillance, all of which may be influenced by endogenous Tau expression. This review examines the current literature on the mechanisms that govern astrocytic Tau regulation, mainly in primary tauopathies with glial cytopathology. Available data indicate that Tau accumulation in these glial cells arises from endogenous synthesis, uptake from neighboring neurons, or a combination of these pathways, while failed extracellular clearance may favor this process by increasing Tau availability in the extracellular space. Once internalized, Tau can be processed, degraded through proteolytic and autophagic-lysosomal pathways, or re-released into the extracellular space, potentially facilitating its propagation; insufficient degradation, in contrast, promotes reactive astrogliosis and disrupts vital processes such as metabolic support and neurotransmitter handling. Taken together, this evidence suggests that distinguishing endogenous synthesis from neuronal uptake is essential to define glial-mediated pathology and recognize astrocytic Tau as a relevant contributor to neurodegenerative disease progression.

Neuroglia doi: 10.3390/neuroglia7030029

Authors: Sangeeta Yanglem Borish Loushambam Sorokhaibam Mexico Singh Sivakumar Vijayaraghavalu

Neurotoxicity is generally thought to result from exogenous agents like environmental chemicals, drugs and biological toxins. However, increasing evidence suggests that many endogenous molecules that play a critical role in normal brain function can become neurotoxic when the regulatory mechanism involved in their production, metabolism, compartmentalization and clearance are disrupted. This shift underlies the basis of endogenous neurotoxicity. This review discusses the major endogenous sources of neurotoxicity: metabolic neurotoxins, dysfunctional neurotransmitters, protein aggregates and inflammatory mediators. These endogenous factors arise from different physiological pathways, but share common pathogenic mechanisms, all of which involve an underlying state of oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxic signalling, neurovascular dysfunction and maladaptive neuroglial responses. This is not a singular process but a network of interconnected processes, which work together to progressively diminish neuronal resilience and promote synaptic dysfunction and neurodegeneration. The review also underscores the critical role of astrocytes, microglia and other glial cells in the maintenance of neuronal homeostasis. By integrating diverse endogenous neurotoxic pathways within a unified homeostasis-centred framework, this review provides a broader perspective on the mechanisms linking metabolic disorders, aging and neurodegenerative diseases. This framework suggests that effective therapeutic strategies may require restoration of physiological regulatory networks rather than targeting individual neurotoxic molecules in isolation. A systems-level understanding of endogenous neurotoxicity may therefore facilitate the development of earlier biomarkers and more effective interventions aimed at preserving neuronal homeostasis and preventing progressive neurological dysfunction.

Neuroglia doi: 10.3390/neuroglia7030028

Authors: Parisa Gazerani Nielsen Santos Pereira Marcos Fabio Henriques dos Santos

Despite remarkable advances in glial biology, the development of effective glia-targeted therapeutics has lagged behind. Accumulating evidence has established glial cells as dynamic regulators of neuroimmune communication, synaptic function, metabolic homeostasis, tissue repair, and disease progression. Advances in single-cell and spatial transcriptomics, molecular profiling, functional imaging, and human-relevant experimental models have revealed remarkable diversity among central and peripheral glial populations, highlighting context-dependent functional states and complex communication networks involving neurons, vascular cells, immune cells, and other glia. These discoveries have expanded therapeutic opportunities while challenging conventional pharmacological strategies that broadly target individual glial cell types or isolated inflammatory pathways. Although numerous pharmacological interventions intentionally or unintentionally modulate glial function, clinical translation has remained limited, highlighting the need for a more integrated therapeutic framework. In this perspective, we critically examine the current landscape of glia-targeted therapeutics through the concept of glial pharmacology, presented as a conceptual framework for understanding how pharmacological interventions modulate glial cells, their functional states, and multicellular communication networks to influence nervous system homeostasis and disease. Rather than providing an exhaustive review, we synthesize the lessons learned from existing therapeutic strategies, discuss the major biological and translational challenges limiting clinical success, and propose guiding principles for the rational development of next-generation glia-targeted therapeutics. We argue that future progress will depend on moving beyond broad cell-specific modulation toward context-dependent therapeutic strategies informed by glial biology, multicellular communication networks, biomarker-guided target engagement, and disease context.

Neuroglia doi: 10.3390/neuroglia7030027

Authors: Norma Serrano-García Alexis Ponce-Juárez Maximiliano Ganado Javier Pérez-Villavicencio Moisés Rubio-Osornio

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the intracellular accumulation of alpha-synuclein (α-syn) aggregates. Historically, research has focused on neuronal mechanisms; however, growing evidence indicates that the progression of neurodegeneration is influenced by changes in the brain microenvironment, particularly through the dynamic interplay between microglia and the extracellular matrix (ECM). ECM in the central nervous system is an organized network of structural proteins, glycoproteins, and proteoglycans that encases neurons and glial cells, regulating processes such as synaptic stability, neural plasticity, and intercellular signaling. In PD, the aggregation of α-syn and neuronal damage induce sustained microglial activation, which can alter ECM structure. Activated microglia release proteases, including matrix metalloproteinases and cathepsins, which can degrade critical ECM components such as collagens, laminins, and proteoglycans. This remodeling can modify synaptic architecture, regulate cellular signaling, and disrupt neuron-glia interactions, fostering an environment conducive to dopaminergic degeneration. Furthermore, ECM remodeling and microglial activation exhibit regional variability within the brain. Regions notably prone to degeneration, such as the SNpc and striatum, display significant alterations in matrix organization and inflammatory activity, while other dopaminergic regions, including the ventral tegmental area, show increased resilience. We suggest that microglia-mediated ECM remodeling serves as a mechanistic link between neuroinflammation and neuronal susceptibility in PD. This review consolidates the existing knowledge on microglial modulation of ECM dynamics during neurodegeneration, explores regional differences in these processes, and evaluates their significance as possible treatment targets.

Neuroglia doi: 10.3390/neuroglia7030026

Authors: Lionete Gall Acosta Filha Carolina Kaminski Sanz Elisa Vieira Rocha Yasmim Almeida Nunes Felipe Silva dos Santos Parisa Gazerani Marcos Fabio Henriques dos Santos

Satellite glial cells (SGCs) play a critical role in the development and maintenance of chronic pain through complex interactions with inflammatory mediators and the opioid pathway. This systematic review synthesizes recent advances in the molecular mechanisms underlying SGC activation and implications for chronic pain management, particularly in conditions associated with the dorsal root ganglia (DRG) and trigeminal ganglia (TG). A systematic search was conducted in four databases (PubMed, Embase, Scopus, and Web of Science) covering studies published between January 2004 and May 2026. After screening 111 records, 19 studies were included. This review highlights how pro-inflammatory cytokines such as IL-1β, IL-1α, and TNF-α, as well as neurotransmitters like ATP and glutamate, contribute to SGC activation, neuroinflammation, and pain modulation. It also explores the role of receptors like CXCR4, TLR4, and P2X7 in SGCs in enhancing analgesic effects and their contributions to opioid tolerance and hyperalgesia. The findings underscore the potential of targeting SGCs to improve pain management outcomes across various pain models, including neuropathic, cancer-related, and visceral pain. Despite promising insights, variability in study methodologies and the complexity of glial–neuronal interactions present challenges. Future research should focus on standardizing experimental protocols and developing targeted therapies to modulate SGC activity to offer hope for patients suffering from chronic pain, particularly in managing opioid tolerance.

Neuroglia doi: 10.3390/neuroglia7030025

Authors: Anass Oukhdouch Maria Dref Youssef Nadir Hayat Bouighajd Wijdane Ait Marzouka Imane Elbah Basma Zinbi Souad Sellami Fatima Ezzahra Hazmiri Hanane Rais

Glioblastoma (GBM), classified as grade 4 of high-grade glioma (HGG) under the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors (WHO CNS-2021), is the most aggressive primary brain tumor in adults. However, with maximal surgical resection, concurrent radiotherapy, and temozolomide (TMZ) chemotherapy, a median patient survival is still between 14 and 16 months. The persistent failure of current treatments is not only traceable to the molecular complexity of tumor cells but is fundamentally shaped by the tumor microenvironment (TME), in which non-neoplastic cells collectively constitute up to half of the total tumor mass. Reactive astrocytes, microglia, tumor-associated macrophages (TAMs), and oligodendrocyte precursor cells (OPCs) are no longer regarded as passive bystanders but as active architects of tumor progression, immune evasion, and therapy resistance. In this comprehensive review, we systematically describe the molecular mechanisms of glial–tumor crosstalk across all three major glial cells. Reactive astrocytes sustain tumor invasion and chemoresistance through connexin-43 gap junctions, bidirectional IL-6/JAK-STAT3 paracrine signaling, and extracellular vesicle-mediated oncogenic reprogramming. Microglia and TAMs undergo profound transcriptional reprogramming via PI3K/Akt/mTOR and CSF-1R signaling, adopting immunosuppressive states that exclude cytotoxic T cells, maintain glioma stem cell (GSC) niches, and drive angiogenesis. OPCs are now underexplored, accumulate at the tumor border, and cooperate with macrophages via Notch and Wnt/β-catenin pathways to establish a therapy-resistant GSC niche at the precise site of post-surgical recurrence. We further address glial–glial interactions as an independent regulatory layer and integrate recent spatial transcriptomic (ST) results revealing a structured, multi-glial niche that governs drug penetration. Finally, we critically evaluate emerging therapeutic strategies targeting these glial–tumor interfaces, including CSF-1R inhibitors, STAT3 modulators, CD47/SIRPα blockades, and engineered extracellular vesicle-based delivery systems. Understanding and targeting the glial ecosystem is an inseparable new field to explore.

Neuroglia doi: 10.3390/neuroglia7030024

Authors: Sara M. Stump Joseph F. Bohlen BaDoi Phan Brady J. Maher

Background/Objectives: Transcription factor 4 (TCF4) is a proneural basic helix–loop–helix transcription factor that plays a critical role in brain development and is associated with a variety of psychiatric disorders, including autism spectrum disorder (ASD), major depressive disorder, and schizophrenia. Autosomal dominant mutations in TCF4 result in a profound neurodevelopmental disorder called Pitt–Hopkins Syndrome (PTHS). Germline TCF4 loss-of-function (LOF) studies using human and mouse models have identified dysregulation in neural cell proliferation, genesis, and specification, which leads to disruption in neuronal, astroglial, and oligodendroglial lineages. In this study, we focused on the role of TCF4 in the genesis of the astrocyte lineage, specifically in the context of modeling PTHS. Methods: We investigated the expression of astrocyte marker genes in primary astrocyte cultures and whole-brain lysates, as well as assessed pan- and subclass-specific astrocyte markers, using immunohistochemical (IHC) analysis in a heterozygous mouse model of PTHS. Lastly, we tracked ventrally derived astrocytes using an Nkx2.1 reporter mouse to investigate misallocation of ventrally derived astrocytes into the dorsal cortex, a phenotype previously observed when both Tcf4 alleles were conditionally deleted in the Nkx2.1 lineage. Results: We show that germline heterozygous mutations in Tcf4 had no effect on the expression of astrocyte markers via qPCR or astrocyte cell density with IHC analysis. Germline heterozygous Tcf4 LOF also did not result in misallocation of ventrally derived astrocytes into the dorsal cortex. Conclusions: These data indicate that germline heterozygous TCF4 LOF, which models PTHS, does not appear to significantly affect the astrocyte lineage at the cell population level.

Neuroglia doi: 10.3390/neuroglia7030023

Authors: Javier Pérez-Villavicencio Omar Villa-Robledo Ximena Megchun-Vázquez Fernando Uriarte-Jiménez Moisés Rubio-Osornio Norma Serrano-García

Huntington’s disease (HD) has traditionally been conceptualized as a neuron-centric disorder primarily attributed to cell-autonomous toxicity of mutant huntingtin (mHTT) in striatal medium spiny neurons. However, this framework inadequately explains the prolonged presymptomatic phase, selective network vulnerability, early non-motor manifestations, and limited success of neuron-targeted therapeutic interventions. Accumulating evidence from molecular biology, transcriptomics, neuroimaging, and preclinical therapeutics supports a reframing of HD as a disorder of neuroglial systems dysfunction. We synthesize data demonstrating that astrocytes, microglia, and oligodendrocyte lineage cells are not passive bystanders but play direct and interactive roles in HD pathogenesis through defined molecular mechanisms. Expression of mHTT in glial populations impairs synaptic homeostasis, metabolic coupling, immune resolution, and myelin integrity, generating self-amplifying pathological feedback loops that destabilize neural circuits long before overt neuronal death. Critically, we evaluate glial replacement therapy as a potential disease-modifying strategy. Preclinical studies demonstrate that transplantation of healthy human glial progenitor cells substantially ameliorates motor, cognitive, and neuropathological deficits in multiple HD models through oligodendroglial remyelination and lactate-mediated metabolic support, despite persistent neuronal mHTT expression. Effective HD therapy will likely require strategies that jointly target the genetic cause and the dysfunctional neuroglial microenvironment. By integrating systems neuroscience with glial biology and translational strategy, this review defines a neuroglial framework for HD that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration.

Neuroglia doi: 10.3390/neuroglia7030022

Authors: Francisco Jonathan Pérez-Delgado Olimpia Ortega-Fimbres Miguel Angel Valencia-Nuñez Diana Monge-Sanchez Miriam Denisse García-Villa Angeles Edith Espino-Saldaña Daniel Reyes-Haro J. Abraham Domínguez-Avila Gustavo A. González-Aguilar Marco Antonio López-Torres Enrique De La Re-Vega Marcelino Montiel-Herrera

Background: Short-chain fatty acids (SCFAs) are metabolites produced by the gut microbiota after fiber fermentation. Some SCFAs, such as acetate, propionate, and butyrate, have been recognized as essential for human health, especially for the brain; however, the cellular mechanisms activated by these molecules in food-intake-related organs, such as the olfactory bulb, remain unclear. Objective: This study evaluates the effects of acetic acid (AA) and sodium butyrate on the physiology of Ca2+ metabolism in olfactory bulb cells (OBCs). Methods: Primary OBC cultures of the postnatal rat (P7-21) were made, and Ca2+ imaging experiments were performed to record the intracellular Ca2+ responses (iCaR) elicited by the application of AA and sodium butyrate (100 nM–1 mM). Immunocytochemical analyses were performed to identify GFAP+ cells and GPR41 and GPR43 receptors in OBCs. Endpoint RT-PCR analyses were made to identify GPR41 and GPR43 transcripts in OBCs. Results: Fewer than 10% of the OBCs tested responded to the application of AA and sodium butyrate with iCaR. Pharmacological studies (20 µM 2-aminoethyl diphenylborinate (2-APB); 10 nM GLPG0974, 120 nM AR420626) showed that iCaR were independent of inositol triphosphate (IP3)-signaling pathways and that OBCs expressed both GPR41 and GPR43 receptors. Endpoint RT-PCR studies performed in both olfactory bulbs and primary OBC cultures confirmed the expression of the GPR41 receptor. Conclusions: This study shows that AA and butyrate induce intracellular Ca2+ responses activated by GPR41 and GPR43 receptors in a discrete cellular population of the rat olfactory bulb.

Neuroglia doi: 10.3390/neuroglia7030021

Authors: Petra Yeboah Ruoli Chen

Ischaemic stroke induces a dynamic neuroimmune response in which microglia act as central regulators of both secondary injury and tissue repair. In the acute phase, microglial activation amplifies neuronal damage through inflammatory signalling and vascular dysfunction; over subsequent days, these cells undergo coordinated transcriptional and metabolic reprogramming toward reparative states. The repeated failure of immunomodulatory therapies in clinical translation, however, suggests that current approaches fundamentally mischaracterise the underlying biology. We propose that microglial state transitions are governed not by discrete linear pathways but by a coupled regulatory network integrating proteostatic clearance, receptor-mediated signalling, inflammasome activation, and intracellular metabolism. Within this network, impaired clearance of cellular debris sustains exposure to damage-associated molecular patterns, perpetuating inflammasome activity and a pro-inflammatory metabolic programme; conversely, restoration of clearance capacity shifts network equilibrium toward resolution and repair. Microglial phenotypes therefore emerge from dynamic shifts in network state rather than progression through fixed activation stages. This framework accounts for the limited efficacy of non-selective or temporally misaligned interventions and identifies the post-acute transitional phase as a window of maximal network plasticity. Aligning therapy with the temporal and functional dynamics of this network—guided by phase-specific biomarkers—provides a mechanistic basis for precision immunomodulation and improved clinical translation in ischaemic stroke.

Neuroglia doi: 10.3390/neuroglia7030020

Authors: Ivana Sivakova Anna Perzelova Stefan Polak

Background/Objectives: The traditional classification of astrocytes was based on morphological differences between astrocytes and their location in brain tissue. Astrocytes stained by impregnation techniques were divided into protoplasmic and fibrous astrocytes. We still use this classification, often supplemented by GFAP immunostaining. However, protoplasmic astrocytes have been found in the human cerebral cortex as GFAP-negative cells. Methods: In this study, astrocytes were identified using Cajal’s gold sublimation method and GFAP immunostaining. Biopsy samples of normal brain tissue (n = 25) were obtained from adult patients diagnosed with traumatic brain injury, stroke, gliomas and brain metastases. Results: In all samples, GFAP-positive fibrous astrocytes were found in the subpial region (layer I-I) and in the white matter. GFAP-positive protoplasmic astrocytes were absent or occurred only rarely in the cortical gray matter (layer III–VI) in samples from patients diagnosed with a tumor. Similar staining was also observed using the Cajal method. However, in samples from patients with traumatic brain injury accompanied by high intracranial pressure, GFAP-positive areas with numerous astrocytic processes and cells with a morphology similar to protoplasmic astrocytes were found. Conclusions: We can conclude that protoplasmic astrocytes are GFAP-negative cells that respond to brain injury by GFAP expression. We consider this finding to be a sign of protoplasmic astrocyte differentiation. On the other hand, fibrous astrocytes are GFAP-positive and respond to brain injury with increased GFAP expression. These results raise questions regarding the classification of astrocytes and, in particular, the histological visualization of the neuro-glial-vascular unit.

Neuroglia doi: 10.3390/neuroglia7030019

Authors: Richard E. Kast Iacopo Sardi Erasmo Barros da Silva Marc-Eric Halatsch

We analyze data indicating that a set of currently marketed FDA/EMA-approved drugs used to treat parkinsonism, extrapyramidal side effects of antipsychotic drugs, or overactive bladder may have the potential to slow the growth of glioblastoma; diffuse midline glioma, H3K27-altered (DMG); and a particular form of DMG growing in the pons of children, diffuse intrinsic pontine glioma (DIPG). These gliomas are typically associated with poor prognosis. Clinical trials evaluating conventional chemotherapeutic drugs have failed to improve DIPG survival. Our analysis of the biochemistry and physiology of DMG and DIPG concludes that neuronal acetylcholinergic agonisms at muscarinic receptors M1 and M3 on primitive oligodendrocyte precursor cells (OPCs) are trophic, growth-stimulating factors in DMG/DIPG growth. A set of muscarinic receptor inhibitors—benztropine, biperiden, and trihexyphenidyl—is used clinically to treat Parkinson’s disease or the parkinsonian side effects from antipsychotic medicines. Another muscarinic inhibitor, oxybutynin, is used to treat overactive bladder. All four drugs may impose dose-related side effects inherent to muscarinic receptor inhibition, such as xerostomia, asthenia, and mild cognitive impairment. We recount the evidence for the inhibition of OPC proliferation and migration mediated by these four M1/M3 inhibitors and report details on the rationale for selecting oxybutynin as the primary candidate for adjuvant therapy in DMG/DIPG. We chose oxybutynin as the first choice to study in DMG and DIPG compared to other antimuscarinic drugs based on its (i) high brain-tissue concentration, (ii) relatively stronger M3 inhibition, (iii) lower side-effect propensity than scopolamine, (iv) wide availability, and (v) the absence of H1 antihistamine or dopaminergic effects. Given the rapidly fatal nature of DMG and DIPG, the potential of oxybutynin for growth slowing may outweigh the associated risks and mild side-effect burdens.

Neuroglia doi: 10.3390/neuroglia7030018

Authors: Javonte S. Thelwell Aaron J. Johnson

Hypoxia is a prevalent characteristic of neurological diseases, including ischemic injury, neurodegeneration and infectious disease complications. Concurrently, hypoxia shapes both protective and pathological responses within the central nervous system (CNS). Central to this process is hypoxia-inducible factor 1α (HIF1α), a transcription factor that regulates cellular adaptation to reduced oxygen availability through coordinated glycolytic, inflammatory and cell survival pathways. Under hypoxic conditions, HIF1α transcriptional activity influences microglial activation, mitochondrial quality control, and cytokine production, thereby modulating neuroinflammation and neuroprotection. Preclinical evidence points toward hypoxia preconditioning being neuroprotective through HIF1α-dependent mechanisms in a context-dependent matter. This review synthesizes the current understanding of the role of HIF1α across neurological disease contexts, highlighting the intersection of hypoxia, neuroinflammation and neuronal survival. Ultimately, defining the cell-specific and context-dependent involvement of HIF1α will be critical for targeted therapeutic approaches to alleviate neuronal death and slow disease progression.

Neuroglia doi: 10.3390/neuroglia7020017

Authors: Vinicius Jose Silva Osterne Messias Vital Oliveira Vanir Reis Pinto-Junior Francisco Sulivan Bastos Mota Rodrigo Bainy Leal Benildo Sousa Cavada Kyria Santiago Nascimento

Autism spectrum disorder is increasingly linked to altered microglial biology. However, current research models are limited by outdated descriptions of microglial “activation”. Here, we propose that microglial involvement in ASD is best understood as a problem of state mismatch, in which temporally programmed and regionally specialized microglial states fail to align with local developmental demands. We synthesize evidence across genetic models, human transcriptomics, and experimental systems to examine three axes of misalignment: developmental timing, circuit specificity, and functional phenotype. These mismatches produce divergent outcomes, including both excessive and insufficient synaptic pruning, and reflect a decoupling between microglial activation markers and effector capacity. We further evaluate molecular recognition systems governing microglia–synapse interactions, with emphasis on complement signaling and glycan-mediated pathways such as sialic acid–Siglec signaling and polysialylation. While glycosylation is not a universal driver of ASD pathology, it represents a plausible regulatory layer controlling synapse visibility and microglial engagement. This framework reconciles conflicting findings in the literature and positions microglia as dynamic developmental effectors whose misaligned state trajectories contribute to circuit-level dysfunction in ASD.

Neuroglia doi: 10.3390/neuroglia7020016

Authors: Nikola Ilić Adrijan Sarajlija

Pediatric neurodevelopmental disorders (NDDs) encompass a highly heterogeneous group of conditions characterized by complex interactions among genetic, molecular, developmental, and environmental factors. Growing evidence increasingly supports an important role for neuroglial dysfunction, including disturbances in astrocytic, microglial, and oligodendroglial biology, in the pathophysiology of disorders such as autism spectrum disorder, global developmental delay, intellectual disability, and rare neurogenetic syndromes. At the same time, artificial intelligence (AI)-assisted analytical approaches are becoming increasingly relevant in pediatric diagnostics through integration of multidimensional datasets, including clinical phenotypes, neuroimaging, genomic sequencing, and molecular biomarkers. This review examines the evolving intersection of neuroglial biology and AI-based analytical methods in pediatric NDDs. Current understanding of neuroglial mechanisms underlying disease vulnerability and developmental heterogeneity is discussed alongside emerging applications of machine learning, deep phenotyping platforms, radiogenomics, and large language models in diagnostic interpretation and clinical decision support. Important translational and ethical challenges, including algorithmic bias, interpretability limitations, data governance, and disparities in data accessibility, are also considered. Overall, integration of neuroglial research with AI-assisted analytical frameworks may contribute to more biologically informed interpretation of pediatric neurodevelopmental disorders and support ongoing development of increasingly individualized diagnostic approaches.

Neuroglia doi: 10.3390/neuroglia7020015

Authors: Érica Novaes Soares Julita Maria Pereira Borges Luciana dos Santos Freitas Monique Reis de Santana Alexandre Moraes Pinheiro Maria de Fátima Dias Costa Silvia Lima Costa Victor Diogenes Amaral da Silva

Introduction: Rutin is a heterocyclic flavonol glycoside found in plants like apples, citrus fruits and buckwheat, with demonstrated anti-inflammatory properties. However, the molecular mechanisms underlying rutin’s direct effects on microglia, the main immune effector cells in the central nervous system, are not fully understood. The SHH/GLI-1 pathway is a neuronal repair pathway that modulates microglial activity and cell proliferation. Objective: For better compression of the rutin anti-inflammatory effects, this work evaluated the action of rutin on SHH/GLI-1 regulation. Methodology: For this, primary cultures of microglia from postnatal P0–2 days Wistar rats were stimulated with LPS (1 µg/mL) and/or treated with rutin (0.5–1 µM). Microglia morphology was characterized by immunofluorescence for Iba1. Gene expression of cytokines, inflammasome, glial-derived neurotrophic factors (GDNFs), and Sonic Hedgehog and family zinc finger-1 (SHH/GLI) were evaluated by real-time qPCR. Result: The results demonstrated that rutin inhibited the LPS-induced inflammatory response in microglia regulating negatively TNF-alpha, IL-6, and NLR family pyrin domain-containing 3 (NLRP3) mRNA expression. In addition, rutin increased GDNF and SHH-GLI-1 mRNA expression. Furthermore, conditioned medium from rutin-treated microglia showed a protective effect on PC-12 cells against LPS-induced cytotoxicity, reducing cell death as measured by the propidium iodide test and preserving cell morphology. Conclusions: This is the first evidence of the effect of rutin in SHH-GLI-1 signaling, contributing to the understanding of its pharmacological mechanisms and potentially revealing new molecular targets for treatment of neuroinflammatory diseases.

Neuroglia doi: 10.3390/neuroglia7020014

Authors: Abba Musa Abdullahi Usama Ishaq Abdulrazaq Ibrahim Muhammad Abdullahi

Background: Neuroinflammation is increasingly recognized as a central mechanism in the pathogenesis of epilepsy, particularly drug-resistant epilepsy (DRE), where conventional anti-seizure medications fail to achieve adequate control. Microglia, the resident immune cells of the central nervous system, play a critical role in mediating inflammatory responses that contribute to seizure initiation, propagation, and pharmacoresistance. Persistent microglial activation promotes the release of pro-inflammatory mediators, exacerbating neuronal hyperexcitability and epileptogenesis. Objectives: This scoping review aimed to systematically map the existing evidence on microglial activation in DRE and to identify emerging therapeutic strategies targeting microglia-mediated neuroinflammation. Methods: The review was conducted in accordance with Joanna Briggs Institute (JBI) methodology and reported following PRISMA-ScR guidelines. A comprehensive search of PubMed, PubMed Central, Scopus, Google Scholar, Embase, and Web of Science was performed without date restrictions. Eligible studies included preclinical, clinical, and review articles investigating microglial activation, neuroinflammatory pathways, or microglia-targeted therapies in epilepsy. Data were charted and synthesized using a narrative approach. Results: A total of 521 records were identified, of which 53 studies met the inclusion criteria after screening and full-text review. The included studies, published between 1998 and 2021, demonstrated a growing research interest in microglia-related mechanisms in epilepsy. Evidence consistently highlighted the role of microglial activation in promoting neuroinflammation and seizure persistence. Emerging therapeutic strategies included anti-inflammatory pharmacotherapies, microglial modulators, cannabinoid-based interventions, gene therapy, and stem cell-based approaches. Conclusions: Targeting microglial activation represents a promising and evolving therapeutic strategy for DRE. While preclinical and early clinical evidence is encouraging, challenges related to specificity, timing, and translational applicability remain. Future research should focus on precision-based interventions to optimize clinical outcomes and enable disease modification beyond seizure control.

Neuroglia doi: 10.3390/neuroglia7020013

Authors: Shilpitha Kadiyala Miraj K. Vakil Heping Zhou

Background: Endotoxin tolerance describes the phenomenon whereby prior lipopolysaccharide (LPS) exposure attenuates inflammatory responses to subsequent LPS challenge. Studies have reported the involvement of different mediators of the toll-like receptor (TLR)-4 signaling pathway in endotoxin tolerance. Methods: We first examined dose- and time-dependent production of cytokines following LPS treatment and then examined cytokine production in BV2 cells pretreated with 5 ng/mL LPS for 24 h, followed by secondary challenge with 1 µg/mL LPS for four hours. To examine which inflammatory cytokine could induce tolerance, we pretreated BV2 cells with 1 µg/mL IL-1β, IL-6, or TNF-α for 24 h, followed by secondary challenge with 1 μg/mL LPS for four hours, and then examined cytokine production by ELISA. Results: Our data showed that LPS induced dose- and time-dependent production of IL-1β, IL-6, and TNF-α. Pretreatment with 5 ng/mL LPS significantly reduced the production of IL-1β and TNF-α in response to secondary challenge, while IL-6 production was slightly enhanced. We also found that pretreatment with IL-1β did not attenuate production of TNF-α but slightly enhanced IL-6 following secondary challenge with 1 µg/mL LPS. In contrast, pretreatment with IL-6 or TNF-α significantly attenuated subsequent LPS-induced IL-1β production without affecting the production of the other. Conclusions: Endotoxin tolerance in BV2 microglial cells selectively suppresses IL-1β and TNF-α while preserving IL-6 production. Both IL-6 and TNF-α independently induce tolerance specifically to IL-1β, suggesting negative feedback regulations. These findings reveal that endotoxin tolerance involves selective rather than global suppression of inflammatory mediators and cross-regulation between LPS and cytokine-induced signaling pathways.

Neuroglia doi: 10.3390/neuroglia7020012

Authors: Alfredo Sanabria-Castro José David Villegas-Reyes Verónica Madrigal-Gamboa Roxana Chin-Cheng

Background: Neuromyelitis optica spectrum disease (NMOSD) is a severe and highly disabling autoimmune astrocytopathy in which humoral immunity, mediated by the presence of autoantibodies, and cellular immunity, through Th17 cells and related cytokines, are key contributors to the pathogenesis. This neuroglial disease affects the central nervous system and is predominantly described in the young productive population. For many years, NMOSD treatment lacked disease-specific therapies and relied on conventional immunosuppressive agents. Progress in elucidating underlying mechanisms of the disease has led to the development and approval of highly specific and effective pathology-modifying drugs. Objective: The objective of this paper is to analyze current and emerging monoclonal antibody-based therapies for NMOSD. Methods: A systematic review of the literature was conducted focusing on approved and investigational monoclonal antibodies targeting major immunopathogenic pathways in NMOSD. Both long-term maintenance therapies and treatments for acute relapses were considered. Results: Targeted monoclonal antibody therapies have significantly transformed the therapeutic management of NMOSD. Drugs directed at B-cell depletion, IL-6 receptor inhibition, and complement blockade have demonstrated substantial efficacy in reducing relapse rates and improving clinical outcomes. Emerging therapies and biomolecular engineering represent promising strategies aimed at further modulating disease activity. These treatments offer improved specificity compared with traditional immunosuppressive regimens and contribute to better long-term disease control. Conclusions: The growing understanding of NMOSD immunopathogenesis has led to the development of highly specific monoclonal antibody-based therapies that have substantially redefined long-term maintenance strategies. Emerging biological targets may expand future therapeutic options. Continued research is essential to optimize individualized treatment approaches and improve outcomes for patients with NMOSD.

Neuroglia doi: 10.3390/neuroglia7020011

Authors: Enes Demir Meriem Boukhiam Mohammad Rashad Ammar Saloum Victor Akinyemi Deondra Montgomery Michael Karsy

The discovery of the glymphatic system (GS) transformed understanding of central nervous system homeostasis by revealing a brain-wide network that facilitates cerebrospinal and interstitial fluid exchange along perivascular pathways. This system clears metabolic waste and maintains the precise ionic environment required for neuronal function through the coordinated action of astrocytic aquaporin-4 channels and intact perivascular architecture. Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, alters physiological barriers through pathological angiogenesis, compression of perivascular spaces, depolarization of aquaporin-4 at astrocytic endfeet, and obstruction of venous and lymphatic drainage. This narrative review synthesizes current experimental and clinical literature identified through targeted searches of PubMed and Scopus to examine interactions between glioblastoma, glymphatic system dysfunction, and tumor microenvironmental changes. To minimize selection bias, studies were categorized according to evidence source and experimental design. Evidence from rodent models and advanced imaging demonstrates as tumor growth impairs glymphatic function, the resulting dysfunction promotes tumor progression by enabling accumulation of pro-tumorigenic growth factors, inflammatory mediators, and acidic metabolites, while elevated interstitial fluid pressure limits drug delivery. Impaired antigen drainage further diminishes immune surveillance, contributing to the immunosuppressive microenvironment that limits immunotherapy efficacy. A critical evaluation of these mechanisms highlights how the glymphatic system influences disease progression and suggests novel avenues for diagnostic imaging and therapeutic intervention. Although significant challenges remain in modeling human fluid dynamics, understanding these hidden networks offers a promising frontier for strategies aimed at restoring cerebral clearance and improving clinical outcomes.

Neuroglia doi: 10.3390/neuroglia7010010

Authors: Md. Aktaruzzaman Md. Ahsan Abid Md. Asaduzzaman Rakib Md. Sazzadul Islam Humayra Afroz Dona Afrida Tabassum Nazmul Hossain Sabekun Nahar Sezin Chowdhury Lutfun Nahar Metu Md. Obayed Raihan

The coronavirus disease 2019 (COVID-19) pandemic has been associated with a wide range of neurological complications, among which persistent cognitive impairment and memory deficits are increasingly recognized as key symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID). Although clinical and epidemiological studies have documented these symptoms across diverse patient populations, the underlying neurobiological mechanisms remain incompletely understood. Growing evidence from human studies, neuropathological analyses, and experimental models indicates that neuroimmune and inflammatory processes plays a central role in COVID-19-associated cognitive dysfunction. As the brain’s resident immune cells, microglia are vital for synaptic health, neuroplasticity, and memory, yet these processes may be compromised after SARS-CoV-2 infection. Systemic inflammation, blood–brain barrier (BBB) disruption, endothelial injury, and cytokine signaling can induce sustained microglial activation and priming, leading to inflammasome activation, complement-mediated synaptic remodeling, oxidative stress, and impaired hippocampal neurogenesis. These processes collectively disrupt neural circuits involved in learning and memory and may underlie the persistent “brain fog” reported by COVID-19 survivors. This review synthesizes clinical, biomarker, neuroimaging, and mechanistic evidence linking SARS-CoV-2 infection to microglia-mediated neuroinflammation and memory impairment. In contrast to prior reviews that broadly describe neuroinflammation in COVID-19, we integrate multidimensional evidence into a microglia-centric immunovascular framework that highlights converging pathogenic pathways underlying cognitive symptoms. We further discuss emerging biomarkers of glial activation and evaluate current and prospective therapeutic strategies targeting microglial and neuroimmune pathways. Understanding the role of microglial dysregulation in post-COVID cognitive impairment may facilitate the development of targeted interventions to mitigate long-term neurological consequences of COVID-19.

Neuroglia doi: 10.3390/neuroglia7010009

Authors: Antonello Curcio Shervin Espahbodinea Francesco Lacava Giovanni Raffa Antonino Germanò

Background: Schwannomas of the third cranial nerve are exceedingly rare benign tumors, and standardized management guidelines are lacking. Their close relationship with critical neurovascular structures makes diagnosis and treatment challenging, with a significant risk of postoperative neurological deficits. Methods: A systematic review of the literature was conducted according to the PRISMA guidelines, including case reports and clinical studies on oculomotor nerve schwannomas (ONSs). Demographic data, clinical presentation, tumor location, diagnostic methods, treatment strategies, and functional outcomes were analyzed. In addition, an illustrative case treated with a multimodal approach is presented. Results: Ninety-six cases met the inclusion criteria. The mean age at diagnosis was 34 years, with a slight female predominance. The most common presenting symptoms were diplopia and ptosis. Contrast-enhanced magnetic resonance imaging was the diagnostic modality of choice. Surgical resection was the primary treatment in most cases but was associated with worsening oculomotor nerve function in 43.1% of surgically treated patients. Stereotactic radiotherapy demonstrated favorable tumor control with lower neurological morbidity. In the presented case, subtotal resection followed by stereotactic radiotherapy resulted in sustained tumor stability at the one-year follow-up. Conclusions: Management of oculomotor nerve schwannomas should be individualized. For small or mildly symptomatic lesions, stereotactic radiotherapy appears to be an effective and less invasive option, while surgery should be reserved for large tumors causing a mass effect or progressive neurological deterioration.

Neuroglia doi: 10.3390/neuroglia7010008

Authors: Yuka Endo Eriko Sugano Yuko Seko Tomokazu Fukuda Kitako Tabata Taira Kakizaki Shu Maruoka Takanori Yokoyama Taku Ozaki Lanlan Bai Hiroshi Tomita

Background: The principal glial cells of the retina, Müller glia, play a central role in retinal regeneration in teleost fish and have recently attracted attention as potential sources of neuronal regeneration in mammals. Objectives: In this study, we examined whether SV40-immortalized rat Müller glia could be directed toward neuronal differentiation using a non-genetic approach with defined culture conditions. Methods: Comprehensive transcriptomic profiling by RNA sequencing indicated that changes in culture medium alone could induce transcriptional reprogramming toward a neuronal lineage. Results: Specifically, expression of Müller glia-related genes decreased, while a subset of photoreceptor-related transcription factors and specific genes showed altered expression, suggesting early-stage induction toward a photoreceptor-like fate. This finding suggests that even immortalized cells may exhibit activation of neuronal genes through non-genetic culture interventions. Gene set enrichment analysis further revealed upregulation of pathways related to the synaptic vesicle cycle, metabolic activation, oxidative stress defense, and lysosomal function, consistent with initiation of neuronal differentiation. Conversely, pathways associated with cell cycle regulation and stemness signaling were downregulated, reflecting a transition from a proliferative to a differentiation-prone state. Collectively, these results provide preliminary molecular markers for early neuronal induction and potential targets for chemical screening. Conclusions: Importantly, this strategy enables neuronal-like differentiation of Müller glia without genetic manipulation, offering a safe and cost-effective platform. Overall, our findings may support the development of in vitro models for retinal neuroregeneration and facilitate research toward regenerative therapies for retinal disorders.

Neuroglia doi: 10.3390/neuroglia7010007

Authors: Parisa Gazerani

Satellite glial cells (SGCs) in sensory ganglia are increasingly recognized as active regulators of neuronal excitability and inflammatory signaling involved in pain conditions. In craniofacial and orofacial pain, trigeminal SGCs exhibit stimulus-dependent responses that develop over time and contribute to disease-related plasticity. Additionally, advances in experimental modeling, computational analysis, and data integration have fueled interest in “digital twins” as tools for hypothesis generation and decision support in biomedicine. However, most current biomedical applications are loosely defined and rarely explicitly address glial biology. Here, we propose a digital twin-inspired framework focused on trigeminal satellite glial cells to combine stimulus-response experiments with computational state modeling. Instead of claiming a fully developed digital twin, we describe a hybrid experimental–computational approach where glial activation states are inferred from measurable outputs, iteratively refined, and used to explore what-if scenarios related to pain mechanisms and treatments. These scenarios are intended to guide experimental design and hypothesis prioritization rather than to generate clinical predictions. We detail how this framework could enhance understanding of underlying mechanisms, prioritize potential interventions, and align with New Approach Methodologies (NAMs) and the 3Rs by reducing exploratory animal use. We also discuss key limitations, including biological simplification, uncertainty, and translational challenges. By viewing glial systems as dynamic, updateable entities rather than static readouts, this approach offers a practical and ethically grounded pathway toward more integrated research on craniofacial pain.

Neuroglia doi: 10.3390/neuroglia7010006

Authors: Caroline Machado Tomazelli Alexandre Leite Rodrigues de Oliveira Luciana Politti Cartarozzi

Background/Objectives: Injuries to spinal ventral roots induce complex retrograde reactions that compromise motoneuron survival, synaptic organization, and glial responses, ultimately limiting the potential for regeneration. The endocannabinoid system (ECS) has emerged as a crucial modulator of neuroprotective processes, primarily through the activation of CB1 and CB2. However, the individual and combined contributions of these receptors to post-injury spinal responses remain poorly understood. Here, we examined the effects of selective blockade of CB1 and CB2 receptors in a murine model of ventral root crush (VRC). Methods: Female C57BL/6JUnib mice received daily intraperitoneal injections of the CB1 antagonist AM-251 and/or the CB2 antagonist AM-630 (1 mg/kg) for 14 days post-lesion. At 28 days after injury, spinal cords were analyzed for motoneuron survival (Nissl staining), glial responses (immunohistochemistry for GFAP and Iba-1), and synaptic coverage (immunohistochemistry for synaptophysin). Results: Selective blockade of CB2 receptors led to a marked reduction in motoneuron survival, enhanced microglial activation-associated morphology (morphological classification and Sholl analysis), and decreased synaptic coverage. CB1 blockade produced milder, context-dependent effects. Dual blockade exacerbated all outcomes, indicating complementary CB1/CB2 functions in the spinal microenvironment. Conclusions: Under the conditions tested, CB2 signaling is necessary for motoneuron preservation, limiting microglial activation-associated morphology, and maintaining synaptic coverage after VRC. The knowledge of specific actions of CB1 and CB2 provides mechanistic insight into the neuroprotective potential of endocannabinoid signaling and reinforces its therapeutic relevance for motoneuron preservation and functional recovery after axotomy.

Neuroglia doi: 10.3390/neuroglia7010005

Authors: Agustina Dapueto Silvia Olivera-Bravo Giselle Prunell

Background/Objective: Parkinson’s disease (PD) has long been viewed from a neurocentric perspective; however, increasing evidence indicates that glial dysfunction also contributes to dopaminergic neurodegeneration. Although neurotoxic glial phenotypes have been described in amyotrophic lateral sclerosis and Alzheimer’s disease in vivo models, it remains unclear whether similar states arise in the pathological milieu of PD. This study aimed to determine whether glial cells with intrinsic neurotoxic properties emerge in the substantia nigra pars compacta (SNpc) in a PD context. Methods: The classical 6-hydroxydopamine rat model was used to obtain glial cultures from the ipsilateral, toxin-damaged SNpc. These cultures were characterized by quantifying cell number and morphology, as well as by assessing the expression of glial markers. Their neurotoxic potential was evaluated in vitro through co-cultures with PC12 cells, and in vivo by transplanting the isolated cells into the SNpc of naïve rats. Assessments included PC12 cell survival, and integrity of the nigrostriatal pathway and motor performance in the cylinder test. Results: Ipsilateral SNpc cultures yielded 25-fold more cells than contralateral controls. Cultured cells co-expressed astrocytic and microglial markers, thus defining a population of damage-derived reactive glia (DDRG). When co-cultured, DDRG reduced PC12 cell survival, whereas control glial cells showed no neurotoxic effects. In vivo, DDRG transplantation induced a dose-dependent loss of dopaminergic neurons and motor impairments, while vehicle and control glia produced no detectable effects. Conclusions: Our findings suggest that glial cells emerging from a neuroinflammatory/neurodegenerative environment in the SNpc may contribute to dopaminergic neuron loss. Within the context of the experimental PD model used, DDRG appears to represent a glial population with potential pathogenic relevance and may constitute a candidate target for further investigation as a therapeutic strategy in Parkinson’s disease.

Neuroglia doi: 10.3390/neuroglia7010004

Authors: Md. Aktaruzzaman Farazi Abinash Rahman Ayesha Akter Md. Hasan Jafre Shovon Al Riyad Hasan Md Mohaimenul Islam Tareq Md. Imtiaz Md. Ali Ahasan Setu Md. Tarikul Islam Nusrat Mahjabin Maha Nazmul Hossain Sabekun Nahar Sezin Rifat Rayhan Sohel Rana Mohammad Jashim Uddin Mohammad Newaz Md. Obayed Raihan

COVID-19 has raised significant concern regarding its neurological impact, particularly during the early pandemic waves when severe systemic inflammation and neuroimmune dysregulation were more common. Although SARS-CoV-2 has been extensively studied, the precise mechanisms underlying its neurological effects remain incompletely understood, and much of the available evidence is derived from early variants with higher pathogenicity. Current research indicates that neuroinflammatory processes—driven primarily by systemic cytokine elevation, microglial activation, and blood–brain barrier dysfunction—contribute to a wide range of neurological symptoms. Severe complications such as encephalopathy, stroke, and cognitive impairment were predominantly reported in critically ill patients infected with the Wuhan, Alpha, or Delta variants, while such manifestations are considerably less frequent in the Omicron era. Most proposed mechanisms, including ACE2-mediated viral entry into the central nervous system, are supported mainly by experimental or preclinical studies rather than definitive human evidence. Biomarkers such as IL-6 and TNF-α, along with neuroimaging modalities including MRI and PET, offer useful but indirect indicators of neuroinflammation. Therapeutic approaches continue to focus on controlling systemic inflammation through immunomodulatory agents, complemented by targeted non-pharmacological strategies—such as physical rehabilitation, cognitive support, and psychological interventions—for the minority of patients with persistent neurological deficits. Overall, current evidence supports a variant-dependent neuroinflammatory profile and underscores the need for longitudinal, mechanism-focused studies to better characterize long-term neurological outcomes and refine therapeutic strategies.

Neuroglia doi: 10.3390/neuroglia7010003

Authors: Moisés Rubio-Osornio Carmen Rubio Maximiliano Ganado Héctor Romo-Parra

The microglia, first identified by Pío del Río-Hortega, are resident macrophages in the CNS that aid in immune monitoring, synaptic remodeling, and tissue repair. Microglial biology’s dual functions in maintaining homeostasis and contributing to neurodegeneration are examined in this review, with a focus on neurodegenerative disease treatment targets. Methods: We reviewed microglial research using single-cell transcriptomics, molecular genetics, and neuroimmunology to analyze heterogeneity and activation states beyond the M1/M2 paradigm. Results: Microglia maintains homeostasis through phagocytosis, trophic factor production, and synaptic pruning. They acquire activated morphologies in pathological conditions, releasing proinflammatory cytokines and reactive oxygen species via NF-κB, MAPK, and NLRP3 signaling. Single-cell investigations show TREM2 and APOE-expressing disease-associated microglia (DAM) in neurodegenerative lesions. Microglial senescence, mitochondrial failure, and chronic inflammation result from Nrf2/Keap1 redox pathway malfunction in ageing. Microglial interactions with astrocytes via IL-1α, TNF-α, and C1q result in neurotoxic or neuroprotective A2 astrocytes, demonstrating linked glial responses. Microglial inflammatory or reparative responses are influenced by epigenetic and metabolic reprogramming, such as regulation of PGC-1α, SIRT1, and glycolytic flux. Microglia are essential to neuroprotection and neurodegeneration. TREM2 agonists, NLRP3 inhibitors, and epigenetic modulators can treat chronic neuroinflammation and restore CNS homeostasis in neurodegenerative illnesses by targeting microglial signaling pathways.

Neuroglia doi: 10.3390/neuroglia7010002

Authors: Greta De Cicco Fausto Chiazza Giada Gibin Borzoni Emanuela Pessolano Valeria Bortolotto Mariagrazia Grilli

Background/Objectives: A healthy lifestyle based on a balanced diet promotes overall well-being and supports brain health, while the consumption of high-energy foods can negatively affect cognitive function, particularly during early developmental stages, such as adolescence. Astrocytes are essential for brain homeostasis, including modulation of neurogenesis in the hippocampus, a region involved in cognitive functions. The impact of short-term high-fat diet (HFD) exposure on astrocytes during adolescence remains unclear. In this study, we examined if brief periods of HFD influence astrocyte morphology, density, and territory volume and, in parallel, the maturation of doublecortin-positive (DCX+) cells in the dorsal hippocampus of adolescent male mice. Methods: We performed 3D reconstructions, analyzed morphometric features as well as other parameters of astrocytes and DCX+ cells following 1 week of HFD (1 w-HFD), 2 weeks of HFD (2 w-HFD), and 1 week of HFD followed by 1 week of return to a low-fat diet (1 w-HFD – 1w-LFD). Results: We observed that 1 w-HFD significantly increased astrocyte morphological complexity and density compared with the control group (1 w-LFD). After 2 w-HFD, astrocyte complexity declined, whereas density was unchanged. Notably, in the 1 w-HFD – 1 w-LFD group, astrocyte complexity was comparable to that of the 2 w-HFD group; density increased compared to both control groups (2 w-LFD and 2 w-HFD). Moreover, both 1 w- and 2 w-HFD impaired granular cell layer (GCL) DCX+ cells density and maturation, and a return to LFD after 1 w-HFD restored maturation but not density. Conclusions: Altogether, these data suggest that short-term HFD exposure has complex effects on GCL astrocytes and impairs DCX+ cell maturation in the dorsal hippocampus of adolescent mice.

Neuroglia doi: 10.3390/neuroglia7010001

Authors: Chloé Mounichetty Fabien Forest Nathalie Perek Frédéric Roche

Introduction: This study investigates how early aging affects the rat brain, focusing on aquaporin-4 and IL-17 levels in the whole brain, as well as glial cell alterations in the hippocampus. The hippocampus, essential for learning and memory, undergoes age-related changes contributing to cognitive decline and neuroinflammation. Glial cells—particularly microglia and astrocytes—are central to these processes. Most research focuses on advanced aging; in this study, we examine early aging effects. Methods: Male Wistar rats (13 weeks and 13 months old) were used. Whole-brain IL-17 and aquaporin-4 levels were assessed by ELISA. Immunohistology targeting GFAP, Iba1, and CD31 was performed on hippocampal sections to assess glial and vascular changes in CA1, CA2/3, and the dentate gyrus (DG). Results: Middle-aged rats brains showed significantly higher IL-17 and aquaporin-4 levels, confirming low-grade inflammation and metabolic alteration. In the hippocampus, microglia, astrocytes, and cerebral microvessels increased in CA2/3, with no significant changes in CA1 or DG. Conclusions: Early aging induces whole-brain neuroinflammation and metabolic changes and region-specific hippocampal alterations, with CA2/3 being particularly susceptible. These findings advance understanding of early brain aging and highlight CA2/3 as a potential target for intervention.

Neuroglia doi: 10.3390/neuroglia6040046

Authors: Shihui Guo Xinyi Yu Hongsheng Zhang

Oligodendrocytes (OLs) constitute the main glial population in the central nervous system and are indispensable for the stability and performance of neural networks. Although best known for generating and maintaining myelin to speed impulse conduction, their influence extends further. By modulating myelin in response to activity, supplying metabolic substrates, and engaging in neuroimmune communication, OLs help preserve the structural integrity and plasticity of neuronal circuits. Growing evidence now positions defective OLs as central players in Alzheimer’s disease (AD). Experimental work suggests that OL injury can act as an early trigger, fostering amyloid-β (Aβ) deposition and Tau hyperphosphorylation. Conversely, toxic Aβ aggregates and pathological Tau proteins damage OLs, causing myelin breakdown and progressive neurodegeneration that fuels a self-perpetuating cycle. Here, we synthesize current knowledge of OL physiology and its multifaceted contributions to AD pathogenesis, with particular attention to the bidirectional interplay between OL dysfunction and the disease’s core features—Aβ and tau. On this basis, we outline prospective therapeutic avenues to protect or restore oligodendrocyte function in AD.

Neuroglia doi: 10.3390/neuroglia6040045

Authors: Asumi Kubo Sara Kamiya Sae Sanaka Kenyu Nakamura Kyoko Kishi Tetsuya Sasaki

Maternal immune activation (MIA) during pregnancy has been associated with increased risk of fetal loss and neurodevelopmental disorders in offspring. This review summarizes recent findings on the effects of MIA on fetal survival and microglial phenotype. Studies using polyinosinic–polycytidylic acid [poly(I:C)-induced MIA mouse models have revealed the crucial role of interleukin-17A (IL-17A) in mediating these effects. Overexpression of RORγt, a key transcription factor for IL-17A production, enhances poly(I: C)-induced fetal loss, possibly due to increased placental vulnerability. Intraventricular administration of IL-17A in fetal brains activates microglia and alters their localization, particularly in periventricular regions and the medial cortex. These activated microglia may contribute to abnormal synaptic pruning and excessive phagocytosis of neural progenitor cells, potentially leading to long-term neurodevelopmental abnormalities. The insights gained from MIA research have important clinical implications, including the potential for early identification of high-risk pregnancies and the development of novel preventive and therapeutic strategies. Future research should focus on elucidating the roles of other cytokines, determining critical periods of MIA susceptibility, and translating findings to human populations, while carefully considering ethical implications and the need for appropriate risk communication.

Neuroglia doi: 10.3390/neuroglia6040044

Authors: Flavio Donnini Giuseppe Minniti Giovanni Rubino Giuseppe Battaglia Pierpaolo Pastina Tommaso Carfagno Marta Vannini Maria Antonietta Mazzei Paolo Tini

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy.

Neuroglia doi: 10.3390/neuroglia6040043

Authors: Francisco Javier Pérez-Martínez Manuel Cifuentes Juan M. Luque

Background: During development, reelin sets the pace of neocortical neurogenesis, enabling newborn neurons to migrate. However, whether—and, if so, how—reelin signaling affects the adult neurogenic niches remains uncertain. Methods: In the present study, we use both loss- and gain-of-function genetic approaches, along with in vivo and ex vivo assays, to investigate this question. Results: We show that reelin signaling, resulting in Dab1 phosphorylation, occurs in the ependymal-subependymal zone (EZ/SEZ) of the lateral ventricles, where, along with its associated rostral migratory stream (RMS), the highest density of functional ApoER2 accumulates. Mice deficient in Reelin, ApoER2, or Dab1 exhibit enlarged ventricles and a dysplastic RMS. Moreover, while the conditional ablation of Dab1 in neural progenitor cells (NPCs) enlarges the ventricles and impairs neuroblast clearance from the SEZ, the transgenic misexpression of Reelin in NPCs of Reelin-deficient mice normalizes the ventricular lumen and the density of ependymal cilia, thereby ameliorating neuroblast migration. Consistently, intraventricular infusion of reelin reroutes neuroblasts. Conclusions: These results demonstrate that reelin signaling persists, sustaining the germinal niche of the lateral ventricles and influencing neuroblast migration in the adult brain.

Neuroglia doi: 10.3390/neuroglia6040042

Authors: Shashikant Patel Roli Kushwaha Debiprasad Sinha Arvind Kumar Sumana Chakravarty

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. Historically, research has focused on neuron-centric models, particularly the monoamine hypothesis. However, the field is now recognizing the critical role of glial cells such as astrocytes, microglia, and oligodendrocytes, establishing them as key contributors to the molecular basis of depression. Rather than serving solely supportive roles, these cells actively modulate neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation are linked to alterations in astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches.

Neuroglia doi: 10.3390/neuroglia6040041

Authors: Rami Shrestha Madhu Babu Pasula Karen Patrice Briski

Background/Objectives: Compartmentalized glucose metabolism in the brain contributes to neuro-metabolic stability and shapes hypothalamic control of glucose homeostasis. Glucose transporter-2 (GLUT2) is a plasma membrane glucose sensor that exerts sex-specific control of hypothalamic astrocyte glucose and glycogen metabolism. Aging causes counterregulatory dysfunction. Methods: The current research used Western blot and HPLC–electrospray ionization–mass spectrometry to investigate whether aging affects the GLUT2-dependent hypothalamic astrocyte metabolic sensor, glycogen enzyme protein expression, and glycogen mass according to sex. Results: The data document GLUT2-dependent upregulated glucokinase (GCK) protein in glucose-deprived old male and female astrocyte cultures, unlike GLUT2 inhibition of this protein in young astrocytes. Glucoprivation of old male and female astrocytes caused GLUT2-independent downregulation of 5′-AMP-activated protein kinase (AMPK) protein, indicating loss of GLUT2 stimulation of this protein with age. This metabolic stress also caused GLUT2-dependent suppression of phospho-AMPK profiles in each sex, differing from GLUT2-mediated glucoprivic enhancement of activated AMPK in young male astrocytes and phospho-AMPK insensitivity to glucoprivation in young female cultures. GS and GP isoform proteins were refractory to glucoprivation of old male cultures, contrary to downregulation of these proteins in young glucose-deprived male astrocytes. Aging elicited a shift from GLUT2 inhibition to stimulation of male astrocyte glycogen accumulation and caused gain of GLUT2 control of female astrocyte glycogen. Conclusions: The outcomes document sex-specific, aging-related alterations in GLUT2 control of hypothalamic astrocyte glucose and ATP monitoring and glycogen mass and metabolism. These results warrant future initiatives to assess how these adjustments in hypothalamic astrocyte function may affect neural operations that are shaped by astrocyte–neuron metabolic partnership.

Neuroglia doi: 10.3390/neuroglia6040040

Authors: Bhavya Vashi Daniel Gonzales-Portillo Jorge Cervantes

Background/Objectives: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with poor survival outcomes. Given the significant financial burden of cancer treatments, repurposing existing drugs can reduce costs and enhance therapeutic efficacy. Metformin, an antidiabetic medication, has been investigated for its antineoplastic effects against GBM. Here, we reviewed the in vitro and in vivo effects of metformin through GBM cell viability and overall animal survival, respectively. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction and statistical analyses were performed using Microsoft Excel, and R. Effect sizes were calculated as standard mean differences (SMDs) for in vitro studies assessing cell viability and hazard ratios (HRs) for in vivo mice survival analyses. Results: A total of two-hundred-thirty in vitro studies and five-hundred-sixty-six in vivo studies were screened. Of these, seven in vitro and eight in vivo studies were compatible for the meta-analysis. The random-effects model showed a reduction in cell viability (SMD [95% CI]: 3.70 [2.28, 5.12]). A pooled in vivo survival analysis suggests an increase in overall survival in mice receiving metformin (p-value = 0.055). A random-effects model for overall survival supports this pooled analysis (HR [95% CI]: 0.76 [0.39, 1.46]). Additionally, metformin also showed a reduction in cell viability (SMD [CI]; 2.27 [0.79, 3.75]) and an increase in overall animal survival (HR [CI], 0.23 [0.12, 0.45]) when it was added as an adjuvant to traditional GBM therapies. Conclusions: Our findings from in vitro and in vivo studies support the potential of metformin as an antineoplastic agent against GBM. We plan to extend our analyses into clinical studies to determine if these benefits extend to human patients. Metformin has the potential to revolutionize GBM therapy if a relationship exists due to its inexpensive nature.

Neuroglia doi: 10.3390/neuroglia6040039

Authors: Sze Jet Aw Jian Yuan Goh Jonis M. Esguerra Timothy S. E. Tan Enrica E. K. Tan Sharon Y. Y. Low

Background: Primary spinal gliomas are rare in the pediatric population. Separately, FGFR1 genomic aberrations are also uncommon in spinal cord tumors. We report a case of a previously well adolescent who presented with progressive symptoms secondary to an intramedullary tumor with unique radiological and molecular characteristics. Case Presentation: A previously well 17-year-old male presented with worsening mid-back pain associated with lower limb long-tract signs. Magnetic resonance imaging (MRI) of his neuro-axis reported a long-segment intramedullary lesion with enhancing foci and a multi-septate syrinx containing hemorrhagic components from C4 to T12. The largest enhancement focus was centered at T7. Additional MRI sequences observed no intracranial involvement or vascular anomaly. He underwent an emergent laminoplasty and excision of the thoracic lesion. Intraoperative findings demonstrated a soft, grayish intramedullary tumor associated with extensive hematomyelia that had multiple septations. Active fenestration of the latter revealed blood products in various stages of resolution. Postoperatively, the patient recovered well, with neurological improvement. Final histology reported a circumscribed low-grade glial neoplasm. Further molecular interrogation via next-generation sequencing panels showed FGFR1 p.K656E and V561M alterations. The unique features of this case are presented and discussed in corroboration with a focused literature review. Conclusions: We highlight an interesting case of an intramedullary tumor with unusual radiological and pathological findings. Emphasis is on the importance of tissue sampling in corroboration with genomic investigations to guide clinical management.

Neuroglia doi: 10.3390/neuroglia6040038

Authors: Aarti Tiwari Satyabrata Rout Prasanjit Deep Chandan Sahu Pradeep Kumar Samal

Astrocytes are the most common type of glial cell in the central nervous system (CNS). They have many different functions that go beyond just supporting other cells. Astrocytes were once thought of as passive parts of the CNS. However, now they are known to be active regulators of homeostasis and active participants in both neurodevelopmental and neurodegenerative processes. This article looks at the both sides of astrocytic function: how they safeguard synaptic integrity, ion and neurotransmitter balance, and blood-brain barrier (BBB) stability, as well as how astrocytes can become activated and participate in the immune response by releasing cytokines, upregulating interferons, and modulating the blood–brain barrier and inflammation disease condition. Astrocytes affect and influence neuronal function through the tripartite synapse, gliotransmission, and the glymphatic system. When someone is suffering from neurological disorders, reactive astrocytes become activated after being triggered by factors such as pro-inflammatory cytokines, chemokines, and inflammatory mediators, these reactive astrocytes, which have higher levels of glial fibrillary acidic protein (GFAP), can cause neuroinflammation, scar formation, and the loss of neurons. This review describes how astrocytes are involved in important CNS illnesses such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia. It also emphasizes how these cells can change from neuroprotective to neurotoxic states depending on the situation. Researchers look at important biochemical pathways, such as those involving toll-like receptors, GLP-1 receptors, and TREM2, to see if they can change how astrocytes respond. Astrocyte-derived substances, including BDNF, GDNF, and IL-10, are also essential for protecting and repairing neurons. Astrocytes interact with other CNS cells, especially microglia and endothelial cells, thereby altering the neuroimmune environment. Learning about the molecular processes that control astrocytic plasticity opens up new ways to treat glial dysfunction. This review focuses on the importance of astrocytes in the normal and abnormal functioning of the CNS, which has a significant impact on the development of neurotherapeutics that focus on glia.

Neuroglia doi: 10.3390/neuroglia6040037

Authors: David Gonzalez Víctor Alarcón Constanza Vásquez-Doorman

Neurodegenerative diseases are characterized by progressive loss of neurons and remain largely incurable. Numerous mammalian models have been developed to study the mechanisms underlying their physiopathology; however, their high cost, complexity and time requirements highlight the need for alternative systems. Glial cells are increasingly recognized as key contributors to neurodegenerative disease progression through non-cell autonomous mechanisms. Planarians possess a nervous system with diverse neuronal subtypes and glial cells, offering an attractive combination of evolutionary conservation and remarkable regenerative capacity. Unlike mammalian glia, planarian glia originate from phagocytic progenitors and exhibit distinctive molecular markers, including if-1, cali and cathepsin. Emerging evidence suggests that planarian glia may contribute to neurotransmitter homeostasis, neuron–glia interactions and phagocytic activity. Additionally, planarians display robust and quantifiable behavioral responses, making them well suited for modeling neurodegenerative disease. In this review, we summarize the current findings regarding neuronal subtypes and glial cells in planaria, emphasizing their relevance as a model system. Further research into planarian glia will be crucial for understanding their roles in pathological contexts and for exploring their potential applications in neurodegenerative diseases research. Planarian simplicity, regenerative capacity, and compatibility with high-throughput approaches position planarians as a powerful model for investigating the cellular and molecular mechanisms underlying neurodegenerative diseases and for identifying potential therapeutic targets.

Neuroglia doi: 10.3390/neuroglia6030036

Authors: Marco Aurelio M. Freire Gabriel S. Rocha Nelson Alessandretti M. Lemos Rafael R. Lima Stanley Bittar Lissandra B. Jenkins Daniel Falcao Harry W. M. Steinbusch Jose Ronaldo Santos

Background/Objectives: Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc). Experimental models that replicate core features of PD are critical to investigate underlying mechanisms and therapeutic strategies. Here we evaluated the effects of an acute unilateral intrastriatal lesion induced by 6-hydroxydopamine (6-OHDA) on neuronal loss and the associated inflammatory response. Methods: Adult male Wistar rats received an injection of 6-OHDA into the right striatum, while the contralateral side received vehicle. Motor behavior was assessed by cylinder and open field tests on post-lesion days (PLDs) 7 and 14. Brains were analyzed by immunohistochemistry for tyrosine hydroxylase (TH), glial response (GFAP and Iba1), and caspase-3 at PLD +14. Results: A marked reduction in TH-immunoreactivity in the lesioned striatum was observed, with ~40% loss of TH-positive neurons in the ipsilateral SNpc. Surviving neurons displayed a 28% increase in soma size compared to the contralateral side. The lesion was accompanied by robust astrocytic and microglial activation at the injection site, as well as enhanced GFAP immunoreactivity in the ipsilateral SN pars reticulata. Apoptotic profiles emerged in the SNpc at PLD +14. Functionally, these alterations were reflected in significant motor asymmetry and decreased locomotor activity. Conclusions: Our findings demonstrate that neuroinflammation accompanies early dopaminergic degeneration following intrastriatal 6-OHDA administration, contributing to motor deficits. Future studies with older animals and broader behavioral and anatomical assessments—including regions such as the ventral tegmental area and motivational or anxiety-related paradigms—may enhance translational relevance.

Neuroglia doi: 10.3390/neuroglia6030035

Authors: Eli J. Futran-Sheinberg Victoria Urbina Sofia Nava Daniel Sanchez Gilberto Guzmán-Valdivia Mario A. Zetter

Neuropeptides (NPs) are small molecular messengers synthesized in large dense core vesicles (LDCVs) and secreted to the extracellular space. In the central nervous system (CNS), NPs are secreted to the synaptic space, playing crucial roles in modulating neurons, astrocytes, microglia, oligodendrocytes, and other glial cells, through G-protein-coupled receptors, thereby influencing complex multicellular responses. During neuroinflammation, NPs regulate glial and neuronal reactions to inflammatory signals, promoting resolution and preventing chronic, non-resolving inflammation. For example, NPs inhibit apoptosis in neurons and oligodendrocytes while inducing anti-inflammatory effects in microglia and astrocytes, modulating cytokine secretion. Here, we present the notion that neuropeptides could participate in neuroinflammatory progression, altering glial responses, leading to excessive, non-resolutive inflammation when dysregulated. NP signaling—whether excessive or deficient—can disrupt specific cellular processes, leading to pathological inflammation, gliosis, and functional loss—hallmarks of neurodegenerative diseases. Despite their significance, the precise mechanisms underlying NP-mediated effects remain incompletely understood. This review synthesizes experimental and translational evidence highlighting the pivotal role of NPs in resolving neuroinflammation and explores how targeting NPs or their receptors could offer novel therapeutic strategies for neurodegenerative disorders. Further research is needed to elucidate the specific signaling pathways and receptor dynamics involved, which could pave the way for innovative treatments that address the root causes of these debilitating conditions.

Neuroglia doi: 10.3390/neuroglia6030034

Authors: Samet Çetin Serap Uysal Dilara Girgin Ayşenur Alp Ecem Kiliç Oğulcan Çiray

Neurodevelopmental disorders represent a significant health concern, leading to a wide range of clinical, cognitive, and social impairments. Although the exact causes of these disorders remain unclear, genetic, epigenetic, and environmental factors all contribute to their emergence. Recently, the role of neuroglia in the pathophysiology of these conditions has received increasing attention. Various glial mechanisms (e.g., neuroinflammation, neurotransmitter regulation, gliosis) have been implicated in both shared and distinct features of these disorders. The identification of novel etiological factors may facilitate the development of new therapeutic modalities targeting glial dysfunction. This review provides a comprehensive overview of neuroglia and summarizes the current understanding of neurodevelopmental disorders and co-occurring disruptive behavioral disorders from a glial perspective. Furthermore, gaps in the literature are highlighted, and potential strategies for addressing these gaps and integrating findings into clinical practice are discussed.

Neuroglia doi: 10.3390/neuroglia6030033

Authors: Adam P. Berg Shahroz H. Tariq Carlos C. Flores Micah Lefton Yuji Owada Christopher J. Davis Thomas N. Ferraro Jon M. Jacobs Marina A. Gritsenko Yool Lee Wheaton L. Schroeder Jason R. Gerstner

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

Neuroglia doi: 10.3390/neuroglia6030032

Authors: Luiz Philipe de Souza Ferreira Diego Dias dos Santos Renata Pereira Lourenço José Marcos Sanches Cristiane D. Gil

Pain is a multifactorial phenomenon involving neuronal, immune, and glial components. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with pro-resolving properties, has emerged as a critical modulator of pain. Present in both peripheral and central compartments, AnxA1 acts through the formyl peptide receptor FPR2/ALX to regulate immune responses, modulate nociceptive signaling, and promote tissue homeostasis. Its mimetic peptide, Ac2–26, has demonstrated robust antinociceptive effects in various pain models, including those induced by inflammation, tissue injury, viral infection, and opioid exposure. AnxA1 modulates cytokine expression, inhibits pro-nociceptive pathways such as TRPV1 and CXCL12/CXCR4, and reprograms macrophages. In the central nervous system, it attenuates neuroinflammation and central sensitization. Notably, AnxA1 can exhibit context-dependent effects, contributing to either the resolution or exacerbation of inflammation. This review examines the molecular mechanisms by which AnxA1 bridges the immune and nervous system pathways, highlighting its therapeutic potential in pain management.

Neuroglia doi: 10.3390/neuroglia6030031

Authors: Hossein Chamkouri Sahar Motlagh Mohavi

Microglia and macrophages are critical immune cells within the central nervous system (CNS), with distinct roles in development, homeostasis, and disease. Once viewed as passive bystanders, these cells are now recognized for their dynamic phenotypic plasticity, which enables them to respond to a wide range of physiological and pathological stimuli. During homeostasis, microglia and CNS-resident macrophages actively participate in synaptic pruning, neuronal support, myelin regulation, and immune surveillance, contributing to CNS integrity. However, under pathological conditions, these cells can adopt neurotoxic phenotypes, exacerbating neuroinflammation, oxidative stress, and neuronal damage in diseases such as Alzheimer’s, Parkinson’s, multiple sclerosis, and glioblastoma. This review synthesizes emerging insights into the molecular, epigenetic, and metabolic mechanisms that govern the behavior of microglia and macrophages, highlighting their developmental origins, niche-specific programming, and interactions with other CNS cells. We also explore novel therapeutic strategies aimed at modulating these immune cells to restore CNS homeostasis, including nanotechnology-based approaches for selective targeting, reprogramming, and imaging. Understanding the complex roles of microglia and macrophages in both health and disease is crucial for the development of precise therapies targeting neuroimmune interfaces. Continued advances in single-cell technologies and nanomedicine are paving the way for future therapeutic interventions in neurological disorders.

Neuroglia doi: 10.3390/neuroglia6030030

Authors: Devlina Ghosh Alok Kumar

The oral microbiota, long recognized for their role in local pathologies, are increasingly implicated in systemic disorders, particularly cardiovascular disease (CVD). This review focuses on emerging evidence linking oral dysbiosis to neuroglial activation and autonomic dysfunction as key mediators of cardiovascular pathology. Pathogen-associated molecular patterns, as well as gingipains and leukotoxin A from Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola, Aggregatibacter actinomycetemcomitans, etc., disrupt the blood–brain barrier, activate glial cells in autonomic centers, and amplify pro-inflammatory signaling. This glia driven sympathetic overactivity fosters hypertension, endothelial injury, and atherosclerosis. Crucially, sex hormones modulate these neuroimmune interactions, with estrogen and testosterone shaping microbial composition, glial reactivity, and cardiovascular outcomes in distinct ways. Female-specific factors such as early menarche, pregnancy, adverse pregnancy outcomes, and menopause exert profound influences on oral microbial ecology, systemic inflammation, and long-term CVD risk. By mapping this oral–brain–heart axis, this review highlights the dual role of oral microbial virulence factors and glial dynamics as mechanistic bridges linking periodontal disease to neurogenic cardiovascular regulation. Integrating salivary microbiome profiling with glial biomarkers [e.g., GFAP (Glial Fibrillary Acidic Protein) and sTREM2 (soluble Triggering Receptor Expressed on Myeloid cells 2)] offers promising avenues for sex-specific precision medicine. This framework not only reframes oral dysbiosis as a modifiable cardiovascular risk factor, but also charts a translational path toward gender tailored diagnostics and therapeutics to reduce the global CVD burden.

Neuroglia doi: 10.3390/neuroglia6030029

Authors: Tania Campos-Ordoñez Brenda Nayeli Ortega-Valles Oscar González-Pérez

Hydrocephalus is a neurological disorder caused by cerebrospinal fluid (CSF) accumulation due to impaired production, circulation, or reabsorption from trauma, neurocysticercosis, neoplasms, subarachnoid hemorrhage, or genetic mutations. This review examines glial remodeling in the ventricular–subventricular zone (V-SVZ) and corpus callosum (CC) in response to hydrocephalus, as ventricular enlargement leads to structural alterations that impact cellular composition in the V-SVZ and CC of patients with hydrocephalus. Animal models of hydrocephalus indicate V-SVZ niche remodeling, ependymal thinning, reduced neuroblast proliferation, increased microglia and astrocytes, increased cell death, and enlarged extracellular matrix structures (fractones). Alterations in the corpus callosum encompass a reduction in width, abnormalities in myelin, astrogliosis, microglial reactivity, a decreased expression of myelin-related proteins (MOG and CNPase), and a reduced number of oligodendrocytes. Additionally, this narrative review highlights important cellular and molecular findings before and after CSF diversion surgery. This primary treatment restores the ventricular size but does not completely reverse glial changes, indicating that ongoing neuroinflammatory processes may interfere with neural recovery.

Neuroglia doi: 10.3390/neuroglia6030028

Authors: Borish Loushambam Mirinrinchuiphy M. K. Shimray Reema Khangembam Venkateswaran Krishnaswami Sivakumar Vijayaraghavalu

Brain cancer is a heterogeneous collection of malignant neoplasms, such as glioblastoma multiforme (GBM), astrocytomas and medulloblastomas, with high morbidity and mortality. Its treatment is complicated by the tumor’s site, infiltrative growth mode and selective permeability of the blood–brain barrier (BBB). During tumor formation, the BBB dynamically remodels into the blood–brain tumor barrier (BBTB), disrupting homeostasis and preventing drug delivery. Furthermore, the TME (Tumor Micro Environment) supports drug resistance, immune evasion and treatment failure. This review points out the ways in which nanomedicine overcomes these obstacles with custom-designed delivery systems, sophisticated diagnostics and personalized therapies. Traditional treatments fail through a lack of BBB penetration, non-specific cytotoxicity and swift tumor adaptation. Nanomedicine provides greater drug solubility, protection against enzymatic degradation, target drug delivery and control over the release. Nanotheranostics’ confluence of therapeutic and diagnostic modalities allows for dynamic adjustment and real-time monitoring. Nanotechnology has paved the way for the initiation of a new era in precision neuro-oncology. Transcending the limitations of conventional therapy protocols, nanomedicine promises to deliver better outcomes by way of enhanced targeting, BBB penetration and real-time monitoring. Multidisciplinary collaboration, regulatory advancements and patient-centered therapy protocols customized to the individual patient’s tumor biology will be necessary to facilitate translation success in the future.

Neuroglia doi: 10.3390/neuroglia6030027

Authors: Ayesha Singh Ruoli Chen

Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O2) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke.

Neuroglia doi: 10.3390/neuroglia6030026

Authors: Lucy Mohapatra Deepak Mishra Alok Shiomurti Tripathi Sambit Kumar Parida Narahari N. Palei

Epilepsy is one of the most prevalent chronic medical conditions that really can affect individuals at any age. A broader study of the pathogenesis of the epileptic condition will probably serve as the cornerstone for the development of new antiepileptic remedies that aim to treat epilepsy symptomatically as well as prevent the epileptogenesis process or regulate its progression. Cellular changes in the brain include oxidative stress, neuroinflammation, inflammatory cell invasion, angiogenesis, and extracellular matrix associated changes. The extensive molecular profiling of epileptogenic tissue has revealed details on the molecular pathways that might start and sustain cellular changes. In healthy brains, epilepsy develops because of vascular disruptions, such as blood–brain barrier permeability and pathologic angiogenesis. Key inflammatory mediators are elevated during epileptic seizures, increasing the risk of recurrent seizures and resulting in secondary brain injury. Prostaglandins and cytokines are well-known inflammatory mediators in the brain and, after seizures, their production is increased. These inflammatory mediators may serve as therapeutic targets in the clinical research of novel antiepileptic medications. The functions of inflammatory mediators in epileptogenesis are covered in this review. Oxidative stress also plays a significant role in the pathogenesis of various neurological disorders, specifically epilepsy. Antioxidant therapy seems to be crucial for treating epileptic patients, as it prevents neuronal death by scavenging excess free radicals formed during the epileptic condition. The significance of antioxidants in mitochondrial dysfunction prevention and the relationship between oxidative stress and inflammation in epileptic patients are the major sections covered in this review.

Neuroglia doi: 10.3390/neuroglia6030025

Authors: Cristiano Antonio Dalpizolo Josyane de Andrade Silveira Manuela Bianchin Marcuzzo Vitor Gayger-Dias Vanessa-Fernanda Da Silva Camila Vieira Pinheiro Bruno Pereira dos Santos Tiago Franco de Oliveira Carlos-Alberto Gonçalves Guilhian Leipnitz

Background: Elevated levels of methylmalonic acid (MMA) are observed in the bodily fluids and tissues of patients with methylmalonic aciduria, a metabolic disorder characterized by manifestations such as vomiting, lethargy, muscle weakness, seizures, and coma. Objectives and Methods: To better understand the neuropathological mechanisms underlying this condition, we investigated the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of MMA on antioxidant defenses, citric acid cycle functioning, and glial reactivity in the cerebral cortex and striatum of Wistar rats. Amino acid levels were also quantified. Results: i.p. and i.c.v. administration of MMA decreased reduced glutathione levels and altered the activities of different antioxidant enzymes in the cortex and striatum. The activity of the citric acid cycle enzyme succinate dehydrogenase was diminished in both brain regions by i.p. and i.c.v. administration. Citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities were further inhibited in the striatum. Furthermore, the i.p. administration increased glial fibrillary acidic protein (GFAP) and glucose transporter 1 (GLUT1) levels, whereas i.c.v. administration elevated GFAP and ionized calcium-binding adaptor molecule 1 (IBA1) levels in the striatum, suggesting glial activation. In contrast, no significant changes in glial markers were detected in the cortex. Moreover, synaptophysin levels remained unaltered in both regions. Finally, i.p. administration increased glutamate, glycine, and serine levels and reduced tyrosine concentrations in the striatum. Conclusions: Our findings indicate that oxidative stress, bioenergetic dysfunction, and glial reactivity induced by MMA may contribute to the neurological deficits observed in methylmalonic aciduria.

Neuroglia doi: 10.3390/neuroglia6030024

Authors: Maya N. Abou Chahla

Glial cells exhibit multifaceted functions and represent essential contributors to various physiological processes in the brain, rather than just being silent supportive cells to neurons. Different glial populations of the central nervous system within involved brain regions play various functions, express different proteins, and result in fluctuating effects when altered. Glial cell pathologies were detected in most mental disorders including suicidal behavior. Suicidal behavior represents a health problem of high importance worldwide, where protective measures are required to be taken at many levels. Studies on patients with mental disorders that represent risk factors for suicidal behavior revealed multiple changes in the glia at diverse levels, including variations regarding the expressed glial markers. This review summarizes the role of glia in some psychiatric disorders and highlights the crosslink between changes at the level of glial cells and development of suicidal behavior in patients with an underlying psychiatric condition; in addition, the interplay and interconnection between suicidal behavior and other mental diseases will shed light on the routes of personalized therapy involving the development of glia-related drugs.

Neuroglia doi: 10.3390/neuroglia6020023

Authors: Sushama Jadhav Shreeya Nair Vijay Nema

HIV, primarily targeting CD4 cells, infiltrates the CNS through various mechanisms, including chemokine-mediated signaling and blood–brain barrier disruption, leading to neuroinflammation and neuronal dysfunction. Viral proteins such as gp120, Tat, and Vpr directly induce neurotoxicity, oxidative stress, and mitochondrial dysfunction, exacerbating cognitive deficits and motor impairments observed in HIV-associated neurocognitive disorders (HANDs). Host genetic factors, including CCR5 mutations and HLA alleles, influence susceptibility to HIV-related neurologic complications, shaping disease progression and treatment responses. Advanced molecular and bioinformatics techniques, from genome sequencing to structural modeling and network analysis, provide insights into viral pathogenesis and identify potential therapeutic targets. These findings underscore the future potential of precision medicine approaches tailored to individual genetic profiles to mitigate neurologic complications and improve outcomes in HIV-infected populations. This comprehensive review explores the intricate interplay between HIV infection and neurogenetics, focusing on how the virus impacts the central nervous system (CNS) and contributes to neurocognitive disorders. This report delves into how the virus influences genetic expression, neuroinflammation, and neurodegeneration, offering insights into molecular mechanisms behind HAND.

Neuroglia doi: 10.3390/neuroglia6020022

Authors: Sydney J. Risen Devin Wahl Thomas J. LaRocca Julie A. Moreno

This review synthesizes the emerging understanding of the roles of glial cells and non-coding RNAs (ncRNAs) in the pathogenesis and progression of Alzheimer’s disease and related dementias (ADRDs). ADRDs encompass a spectrum of neurodegenerative disorders characterized by cognitive decline, memory impairment, and functional deterioration. The interplay between the most common types of glial cells—astrocytes, microglia, and oligodendrocytes—and ncRNAs is emerging as a critical factor in the development of ADRDs. Glial cells are essential for maintaining homeostasis within the central nervous system (CNS); however, their dysregulation can lead to neuroinflammation and neuronal dysfunction, exacerbating neurodegeneration. Reactive astrocytes and activated microglia can create neurotoxic environments that further impair neuronal health. Concurrently, ncRNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as significant regulators of glial gene expression, influencing inflammatory responses and glial cell function. Understanding the complex interactions between glial cells and ncRNAs is crucial for developing targeted therapeutic strategies. By elucidating the mechanisms underlying their interactions, this review aims to highlight the critical importance of glial cells and ncRNAs in the context of neurodegenerative diseases, paving the way for innovative approaches to prevent and treat ADRDs. Ultimately, enhancing our understanding of these processes may lead to novel therapies and improved outcomes for individuals affected by these debilitating conditions.

Neuroglia doi: 10.3390/neuroglia6020021

Authors: Stephanie M. Sissons Nirosha J. Murugan Blake T. Dotta

Background/Objectives: Nitric oxide (NO) and electromagnetic fields (EMFs) have been reported to influence central nervous system (CNS) function and organization. This study explores the effects of NO modulation and EMF exposure on neurodevelopment and glial fibrillary acidic protein (GFAP) expression and cell morphology, extending the prior work on perinatal EMF exposure in Wistar rats. Methods: Rats were perinatally exposed to water, 1 g/L L-arginine (LA), or 0.5 g/L N-methylarginine (NMA), along with a 7 Hz square-wave EMF at intensities of 0 nT, ≤50 nT, or 500 nT, starting three days before birth and continuing for 14 days postnatally. GFAP expression and cell morphology were analyzed via immunohistochemistry in regions including the hypothalamus, amygdala, hippocampus, and cortex. Results: Significant changes in GFAP morphology and expression are observed. A main EMF effect emerged in the right ventromedial hypothalamus, where the branch length of GFAP-expressing cells increased in EMF-exposed groups compared to the controls [t(32) = −2.52, p = 0.017]. In the hippocampus, LA exposure decreased GFAP expression in the right dentate gyrus compared to water controls [t(23) = 2.37, p = 0.027]. A sex-specific EMF effect was detected in the left CA2 hippocampus, where males exposed to EMF showed significant differences from unexposed males [t(15) = −2.90, p = 0.011]. Conclusions: These findings reveal complex interactions between EMF exposure, sex, and NO modulation, with region-specific effects on GFAP expression in the developing rat brain.

Neuroglia doi: 10.3390/neuroglia6020020

Authors: Yuyan Zhou Song Qin Haixiang Wu

Müller glia exhibit a remarkable regenerative capacity in zebrafish through spontaneous reprogramming post-injury but remain limited in mammals. This review highlights the key mechanisms underlying Müller glia reprogramming, including gene regulatory networks, cytokine signaling, signal transduction pathways, epigenetic modifications, and transcriptional regulation. Cross-species analyses have uncovered conserved gene networks that suppress neurogenesis in mammals, while injury-induced transcriptional profiles reveal divergent regenerative strategies. Combinatorial approaches may enhance the reprogramming of mammalian Müller glia into functional neurons. Nevertheless, significant challenges remain, such as variability in the efficacy of direct reprogramming methods and the limited regeneration of cone photoreceptors, even in regenerative species. We conclude that targeting epigenetic barriers and species-specific regulatory pathways offers promising avenues for clinical translation in retinal disorders such as glaucoma and retinitis pigmentosa. Moving forward, research efforts should prioritize the functional integration of regenerated neurons and the development of standardized methodologies to accelerate therapeutic advancements.

Neuroglia doi: 10.3390/neuroglia6020019

Authors: Rafael André da Silva André Maurício Passos Liber Luiz Philipe de Souza Ferreira Francisco Manuel Moreno-Carmona Diego Dias dos Santos Monielle Sant’Ana Marcelo Fernandes Costa Dora Fix Ventura Cristiane Damas Gil

Background/Objectives: The annexin A1 (AnxA1) protein has proven important in ocular disease homeostasis and holds great therapeutic promise. However, its role in the context of the healthy retina remains unknown. Therefore, this study used electroretinography (ERG) to investigate the role of endogenous AnxA1 in the retinal function of wild-type (WT) and AnxA1 knockout mice (AnxA1−/−). Methods: An extensive repertoire of full-field ERG was applied to AnxA1−/− and WT mice to examine retinal physiology. Morphometric analyses of the retina were conducted. Results: Our results revealed significant differences in the implicit time of a-wave and b-wave between the WT and AnxA1−/− groups under scotopic conditions. The negative and positive amplitude components of mesopic ON responses were higher in the AnxA1-/- group than in the WT group. In contrast, the implicit time of mesopic ON responses were significantly higher in the WT group than in the AnxA1-/- WT group. However, in photopic OFF responses, only the implicit time was significantly longer in the WT group than in the AnxA1−/− group. In the histomorphometric analysis, the retina of AnxA1−/− mice shows increased thickness. Conclusions: The absence of AnxA1 alters retinal morphology and physiology.

Neuroglia doi: 10.3390/neuroglia6020018

Authors: Enrique Hernández-Arteaga Josué Antonio Camacho-Candia Roxana Pluma-Romo María Isabel Solís-Meza Myriam Nayeli Villafuerte-Vega Francisco Aguilar-Guevara

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition influenced by genetic, environmental, and epigenetic factors, leading to cognitive, emotional, and social impairments. Due to the heterogeneity of ASD, conventional therapies often have limited effectiveness, highlighting the need for complementary interventions. Enriched environments (EEs), characterized by enhanced sensory, cognitive, and motor stimulation, have shown promise in alleviating ASD symptoms. This review examines the role of glial cells in mediating the effects of EE. Methods: A literature review was conducted, analyzing studies on EE interventions in animal models and humans, with a focus on glial involvement in neuroplasticity and synaptic remodeling. Results: Evidence from animal models suggests that EE induces significant glial modifications, including increased synaptogenesis and enhanced neuronal connectivity. Studies in rodent models of ASD have demonstrated that EE reduces stereotypical behaviors, improves social interactions, and enhances cognitive function, effects that are closely associated with astrocyte and microglia activity. Similarly, human studies indicate that EE interventions lead to reduced autism symptom severity and improved cognitive outcomes, further supporting the hypothesis that glial cells play a central role in mediating the beneficial effects of EE. Conclusions: This review highlights the potential of EE as a modulator of the brain’s microenvironment, emphasizing the critical role of glial processes in ASD intervention. These findings suggest that future therapeutic strategies for ASD should integrate approaches that specifically target a glial function to optimize intervention outcomes. However, further research is needed to optimize EE protocols and address ASD heterogeneity.

Neuroglia doi: 10.3390/neuroglia6020017

Authors: Ghaidaa Ebrahim Hunter Hutchinson Melanie Gonzalez Abeer Dagra

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, with increasing evidence supporting the role of immune dysregulation in its pathophysiology. Neuroinflammation, mediated by microglial activation, pro-inflammatory cytokine production, and blood–brain barrier dysfunction, plays a crucial role in dopaminergic neuronal degeneration. Furthermore, peripheral immune changes, including T cell infiltration, gut microbiota dysbiosis, and systemic inflammation, contribute to disease progression. The bidirectional interaction between the central and peripheral immune systems suggests that immune-based interventions may hold therapeutic potential. While dopaminergic treatments remain the standard of care, immunomodulatory therapies, monoclonal antibodies targeting α-synuclein, and deep brain stimulation (DBS) have demonstrated immunological effects, though clinical efficacy remains uncertain. Advances in immune phenotyping offer new avenues for personalized treatment approaches, optimizing therapeutic responses by stratifying patients based on inflammatory biomarkers. This review highlights the complexities of immune involvement in PD and discusses emerging strategies targeting immune pathways to develop disease-modifying treatments.

Neuroglia doi: 10.3390/neuroglia6020016

Authors: Alana Alves Farias Ana Carla dos Santos Costa Jéssica Teles Souza Érica Novaes Soares Cinthia Cristina de Oliveira Santos Costa Ravena Pereira do Nascimento Silvia Lima Costa Victor Diogenes Amaral da Silva Maria de Fátima Dias Costa

In homeostasis, the glial cells support pivotal functions, such as neuronal differentiation, neuroprotection, nutrition, drug metabolism, and immune response in the central nervous system (CNS). Among these cells, astrocytes and microglia have been highlighted due to their role in the pathogenesis of several diseases or due to their role in the defense against several insults (ex., chemicals, and pathogens). In Vitro cytological analysis of astrocytes and microglia has contributed to the understanding of the role of morphological changes in glial cells associated with a neuroprotective or neurotoxic phenotype. Currently, the main tools used for the investigation of glial cell morphology in culture are phase contrast microscopy or immunolabeling/fluorescence microscopy. However, generally, phase contrast microscopy does not generate images with high resolution and therefore does not contribute to visualizing a single cell morphology in confluent cell cultures. On the other hand, immunolabeling requires high-cost consumable antibodies, epifluorescence microscope or confocal microscope, and presents critical steps during the procedure. Therefore, identifying a fast, reproducible, low-cost alternative method that allows the evaluation of glial morphology is essential, especially for neuroscientists from low-income countries. This article aims to revise the use of Rosenfeld’s staining, as an alternative low-cost and easy-to-reproduce method to analyze astrocytic and microglial morphology in culture. Additionally, it shows Rosenfeld’s staining as a valuable tool to analyze changes in neural cell morphology in toxicological studies.

Neuroglia doi: 10.3390/neuroglia6020015

Authors: André Demambre Bacchi

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in the regulation of synaptic transmission, metabolic support, and immune mechanisms within the central nervous system. In addition to their structural role, these cells actively modulate neurotransmitter homeostasis and influence neuronal plasticity, thereby affecting cognition, mood, and behavior. This review discusses how neuroglial alterations contribute to the pathophysiology of five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. We synthesized preclinical and clinical findings illustrating that glial dysfunction, including impaired myelination and aberrant neuroinflammatory responses, often parallels disease onset and severity. Moreover, we outline how disruptions in astrocytic glutamate uptake, microglia-mediated synaptic pruning, and blood–brain barrier integrity may underlie the neurobiological heterogeneity observed in these disorders. The therapeutic implications range from anti-inflammatory agents to investigational compounds that aim to stabilize glial function or promote remyelination. However, challenges due to interindividual variability, insufficient biomarkers, and the multifactorial nature of psychiatric illnesses remain. Advances in neuroimaging, liquid biopsy, and more precise molecular techniques may facilitate targeted interventions by stratifying patient subgroups with distinct glial phenotypes. Continued research is essential to translate these insights into clinically efficacious and safe treatments.

Neuroglia doi: 10.3390/neuroglia6010014

Authors: Deivison Silva Argolo Lucas Matheus Gonçalves de Oliveira Gilles J. Guillemin George E. Barreto Arthur Morgan Butt Silvia Lima Costa Maria de Fátima Dias Costa

The central nervous system (CNS) relies on complex and dynamic interactions between neurons and glial cells. Among glial cells, astrocytes regulate the chemical environment surrounding neurons and supply essential nutrients for brain metabolism whereas microglia, the resident macrophages of the CNS, play critical roles in homeostasis, defense, and responses to injury. Both microglia and astrocytes contribute to the regulation of excitotoxicity and inflammation mediated by the metabolism of tryptophan (Trp) via the kynurenine pathway. Trp metabolism generates several bioactive metabolites, including quinolinic acid (QUIN) and kynurenic acid (KYNA), which have opposing effects. QUIN, produced by activated microglia, acts as an agonist for NMDA receptors; excessive stimulation of these receptors can lead to excitotoxicity and neuronal death. Conversely, KYNA, primarily produced by astrocytes via kynurenine 2,3-aminotransferases (KAT), acts as an NMDA receptor antagonist, conferring neuroprotection by mitigating excitotoxicity. Dysregulation of the Trp metabolism is implicated in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis, as well as in various neuropsychiatric disorders. This review examines the cellular and molecular mechanisms underlying Trp metabolism in glial cells, highlighting the unique contributions of each glial phenotype, the implications for CNS pathologies, and the potential biomarkers and therapeutic targets for restoring homeostasis and preventing disease progression.

Neuroglia doi: 10.3390/neuroglia6010013

Authors: Enes Demir Deondra Montgomery Ammar Saloum Nasser Yaghi Michael Karsy

High-grade gliomas are aggressive, primary, central nervous system tumors with low survival rates due to recurrence and resistance to current therapy models. Recent studies have highlighted the importance between the interaction of glioma cancer cells and cells of the tumor microenvironment (TME). Cancer stem cells and immune cells play a critical role in the TME of gliomas. TMEs in glioma include the perivascular TME, hypoxic TME, and invasive TME, each of which have evolved as our understanding of the involved cellular players has improved. This review discusses the multidimensional aspects of the current targeted therapies and interactions between glioma cells and the TME with specific focus on targeted immunotherapies. Understanding the complexities of the TME and elucidating the various tumor-cell interactions will be critical for facilitating the development of novel precision strategies, ultimately enabling better patient outcomes.

Neuroglia doi: 10.3390/neuroglia6010012

Authors: Fernando da Silva Fiorin Caroline Cunha do Espírito Santo

Background/Objectives: Spinal cord injury (SCI) is a devastating condition that leads to a cascade of cellular and molecular events, resulting in both primary and secondary damage. Among the many cells involved in the post-SCI environment, glial cells in the spinal cord and brain are pivotal in determining the trajectory of injury and repair. Methods: While recent SCI studies have shown changes in the genotype of glial cells following injury, exactly how these alterations occur after damage remains unknown. In this sense, the systemic inflammatory molecules could be involved in the connection between the spinal cord and brain, inducing glial activation by different signaling pathways. Preclinical studies have shown that nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways are involved in the change in glial type. Results: These cells, which include astrocytes and microglia, exhibit dynamic responses following spinal injury, contributing to both neuroprotection and neurodegeneration. These different effects indicate that the molecular environment causes changes in the type of astrocytes and microglia, leading to different actions. Conclusions: Understanding the mechanisms of glial cell activation, it is possible to clarify the roles of these glial cells in pathophysiology and their potential repair mechanisms post-injury.

Neuroglia doi: 10.3390/neuroglia6010010

Authors: Melissa Castillo-Bustamante Andrés Felipe Herrón-Arango María José Bedoya Juan José Figueroa Valeria Rees Alejandro García

Vestibular disorders significantly affect individuals by impairing balance, spatial orientation, and quality of life. Despite the focus on neuronal mechanisms, emerging research emphasizes the importance of neuroglia—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the onset, progression, and resolution of these conditions. This narrative review explores the roles of neuroglia in vestibular disorders, including vestibular migraines and unilateral and bilateral vestibulopathies. It discusses established facts, challenges, and future perspectives, offering insights into their pathophysiological roles and therapeutic implications, and the limitations of current research. By understanding the interplay between neuroglia and vestibular function, this review aims to advance diagnostic and treatment strategies for these disorders

Neuroglia doi: 10.3390/neuroglia6010011

Authors: Nikola Ilic Adrijan Sarajlija

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by challenges in social communication, restricted interests, and repetitive behaviors. Recent studies highlight the crucial roles of neuroglial cells—astrocytes, microglia, and oligodendrocytes—in synaptic function, neural connectivity, and neuroinflammation. These findings offer a fresh perspective on ASD pathophysiology. This review synthesizes current knowledge on neuroglial dysfunction in ASD, emphasizing its role in pathophysiological mechanisms, genetic influences, and potential therapeutic strategies. Methods: We conducted a comprehensive literature review, integrating insights from neuroscience, molecular biology, and clinical studies. Special focus was given to glial-mediated neuroinflammatory mechanisms, synaptic plasticity regulation, and the impact of genetic mutations on neuroglial signaling and homeostasis. Results: Neuroglial dysfunction in ASD is evident in abnormal synaptic pruning by microglia, impaired astrocytic glutamate regulation, and defective oligodendrocyte-driven myelination, which collectively disrupt neuronal architecture. Emerging therapies targeting these pathways, including anti-inflammatory drugs, microglial modulators, and cell-based approaches, show promise in alleviating key ASD symptoms. Additionally, advanced interventions such as gene editing and glial progenitor therapy present opportunities to correct underlying neuroglial dysfunction. Conclusions: This review establishes a comprehensive framework for understanding neuroglial contributions to ASD. By integrating insights from diverse disciplines, it enhances our understanding of ASD pathophysiology and paves the way for novel therapeutic strategies targeting neuroglial pathways.

Neuroglia doi: 10.3390/neuroglia6010009

Authors: Borish Loushambam Sangeeta Yanglem Venkateswaran Krishnaswami Munish Kumar Sivakumar Vijayaraghavalu

Background: Neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and spinal cord injury (SCI) are significant global health challenges due to their complex pathology and limited therapeutic options. Conventional treatments often fail to efficiently cross the blood–brain barrier (BBB), leading to poor bioavailability and systemic toxicity. This narrative review explores the potential of nanomedicine in addressing these limitations and advancing targeted therapies for neural disorders. Methods: This review examines recent studies on the use of engineered nanoparticles (NPs), including liposomes, dendrimers, micelles, and nanogels, for targeted drug delivery and multifunctional theranostics in neural diseases. It evaluates their role in promoting axon regeneration, reducing neuroinflammation, and repairing neural damage. Additionally, innovative applications in gene therapy and RNA-based treatments, such as CRISPR-Cas9 and RNA interference (RNAi), are discussed. Challenges related to toxicity, scalability, affordability, and regulatory barriers are highlighted, along with potential strategies to address these issues. Results: Nanoparticles have shown significant promise in crossing the BBB, delivering therapeutic agents to neural tissues, and minimizing off-target effects. Emerging applications in gene and RNA-based therapies demonstrate their versatility in addressing disease-specific challenges. However, unresolved issues such as long-term safety, manufacturing scalability, and cost continue to pose challenges. Conclusions: Nanomedicine offers a promising approach to overcoming current limitations in the treatment of neural disorders. This review emphasizes the need for continued interdisciplinary efforts to address translational barriers and highlights the potential for nanomedicine to improve the outcomes and quality of life for patients with neural disorders, stroke, and SCI.

Neuroglia doi: 10.3390/neuroglia6010008

Authors: Swagatama Mukherjee Prakash P. Pillai

Background: Angiogenesis is a key factor necessary for tissue growth but becomes often dysregulated in cancer, driving tumour progression. Glioblastoma multiforme (GBM) induces abnormal vascular remodelling via Hypoxia-activated VEGF, FGF and PDGF. Despite increased vascularization, hypoxia persists, worsening malignancy. Additionally, emerging evidence highlights extracellular vesicles (EVs) as key mediators of angiogenesis as conduits transferring bioactive cargo modulating cellular signaling. By promoting neovascularization, EVs can facilitate tumour growth, hinder drug delivery, and contribute to therapeutic resistance, making them potential therapeutic targets. Objective: This study explores the role of GBM-derived EVs in promoting aberrant angiogenesis by modulating VEGF and MMP signalling and correlating them with EV biogenesis to better understand tumour vascularisation and therapeutic paucities. Methods: This study investigates the role of GBM-derived EVs in angiogenesis dysregulation, via in silico and in vitro approaches, making use of available databases to study the enrichment profiles of key angiogenic drivers enriched in GBM and EVs followed by validation studies using 2D cell culture of HUVEC and U87MG cells on treatment with EV inhibitor. Results: We observed that GBM-derived EVs can be key collaborators of promoting angiogenesis by upregulating key pro-angiogenic genes (VEGFA, NRP1, MMP9) and EV biogenesis markers (CD9, CD81, TSG101), facilitating endothelial cell migration and vascular remodelling. Functional assays further confirmed that EVs act as vectors for pro-angiogenic signals, while their inhibition with GW4869 significantly reduced angiogenic activity, highlighting their role in tumour vascularization. Conclusions: Targeting EV-mediated angiogenesis presents a promising therapeutic strategy for GBM, warranting further validation in preclinical and clinical models.

Neuroglia doi: 10.3390/neuroglia6010007

Authors: Dimitar Metodiev Petia Dimova Margarita Ruseva Dimitar Parvanov Rumiana Ganeva Georgi Stamenov Sevdalin Nachev Vesela Ivanova Rumen Marinov Krassimir Minkin

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction.

Neuroglia doi: 10.3390/neuroglia6010006

Authors: Ana Victoria Arredondo-Robles Karen Paola Rodríguez-López Rodolfo Daniel Ávila-Avilés

This review aims to provide a comprehensive overview of the main types, subtypes, clinical manifestations, and current therapeutic strategies for multiple sclerosis, emphasizing recent advancements and clinical challenges. Multiple Sclerosis (MS) is a demyelinating, chronic, autoimmune, and inflammatory disease that affects the Central Nervous System (CNS). Its classification has the following subtypes: Relapsing-Remitting (RRMS), Secondary-Progressive (SPMS), and Primary-Progressive (PPMS), including rarer subtypes such as Clinically Isolated Syndrome (CIS), Radiologically Isolated Syndrome (RIS), Balo’s Concentric Sclerosis (BCS), Schilder’s Disease (SD), and Progressive-Relapsing MS (PRMS). This article divides the various treatments for MS into the following three categories: acute relapse management, symptomatic treatments, and Disease-Modifying Treatments (DMTs). The latter represents revolutionary research in MS, since they are the drugs considered as the best treatment alternatives for this disease.

Neuroglia doi: 10.3390/neuroglia6010005

Authors: Rodrigo Bainy Leal Vanir Reis Pinto-Junior Messias Vital Oliveira Vinicius Jose Silva Osterne Nicole Sartori Ana Carolina dos Santos Ricardo Castilho Garcez Kyria Santiago Nascimento Benildo Sousa Cavada

Gliomas, ranging from low-grade pilocytic astrocytomas to highly malignant glioblastomas, are primary brain tumors that originate from neural or glial stem cells. Classified by the WHO into grades 1 to 4, these tumors exhibit varying prognoses, with oligodendrogliomas and astrocytomas having better and intermediate outcomes, respectively, while glioblastomas are associated with a poor prognosis. Despite advancements in molecular and genetic research that have improved diagnosis and the development of targeted therapies, treating high-grade gliomas remains a significant challenge due to their diffuse nature. In this context, lectins, carbohydrate-binding proteins, have shown promise as diagnostic and therapeutic agents for cancer, including gliomas. Plant lectins, particularly those from legumes, exhibit significant antiproliferative effects on glioma cells. These effects include decreased cell viability and migration, alongside the induction of autophagy and apoptosis, suggesting their potential as therapeutic agents. Although the mechanisms underlying these effects are not yet fully understood, molecular targets and pathways involved in the antiglioma activity of lectins have been identified. Key targets include matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), CD98 (xc- system), AMPA receptor, and CD73. This review focuses on the antiglioma potential of legume lectins, their applications, and the main molecular targets based on their functions, structures, and associated molecular mechanisms.

Neuroglia doi: 10.3390/neuroglia6010004

Authors: Olayemi K. Ijomone Ileje I. Ukwubile Vivian O. Aneke Tobiloba S. Olajide Happiness O. Inyang Omolabake I. Omotosho Toheeb O. Oyerinde Victor E. Anadu Tolulope J. Gbayisomore Oritoke M. Okeowo David A. Oyeniran Olumide A. T. Ogundahunsi Omamuyovwi M. Ijomone

Overexposure of humans to heavy metals and essential metals poses a significant risk for the development of neurological and neurodevelopmental disorders. The mechanisms through which these metals exert their effects include the generation of reactive oxygen species, mitochondrial dysfunction, activation of inflammatory pathways, and disruption of cellular signaling. The function of glial cells in brain development and in the maintenance of homeostasis cannot be overlooked. The glial cells are particularly susceptible to metal-induced neurotoxicity. Accumulation of metals in the brain promotes microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity, inducing alteration in synaptic transmission, cognitive deficit, and neuronal damage. In this review, we highlighted the role of glial dysfunction in some selected neurodegenerative diseases and neurodevelopmental disorders. We further dive into how exposure to metals such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, and lead affect the functions of the microglia, astrocytes, and oligodendrocytes and the mechanisms through which they exert the effects on the brain in relation to some selected neurodegenerative diseases and neurodevelopmental disorders. Potential therapeutic interventions such as the use of new and improved chelating agents and antioxidant therapies might be a significant approach to alleviating these metal-induced glial perturbations.

Neuroglia doi: 10.3390/neuroglia6010002

Authors: Indra R. Bishnoi Evan A. Bordt

Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders.

Neuroglia doi: 10.3390/neuroglia6010003

Authors: Jonhoi Smith Melvin Field Kiminobu Sugaya

Background/Objectives: Glioblastoma (GBM), a highly aggressive grade IV astrocytoma, poses a major therapeutic challenge due to the resistance of cancer stem cells (CSCs) existing within its cell population to the conventional therapies. Recently, we reported that RNA interference targeting CSC protection mechanism significantly improved therapeutic efficacy. However, challenges remain, including limited transfection efficiency in neural cells and the difficulty of crossing the blood–brain barrier (BBB). Methods: In this study, we investigated the potential of exosome-mediated delivery of therapeutic cargo to GBM cells by engineering the exosomes to carry green fluorescent protein (GFP) and expressing brain-homing peptide (BHP) on their surface, which has high affinity to the neural cells. Results: We found that BHP-modified exosomes doubled GFP delivery efficacy from 20% to 40%, outperforming traditional transfection methods like lipofection in vitro. In vivo, BHP-modified exosomes demonstrated an ability to cross the BBB and targeted cargo delivery to brain regions following intranasal and subcutaneous administration. Conclusions: These results underscore the potential of engineered exosomes for efficient cargo delivery to enhance therapeutic efficacy against brain tumors and suggest novel avenues for delivering biomolecules to the brain in the treatment of neurological disorders.

Neuroglia doi: 10.3390/neuroglia6010001

Authors: David Brash-Arias Luis I. García Gonzalo Aranda-Abreu Rebeca Toledo-Cárdenas César Pérez-Estudillo Donaji Chi-Castañeda

Astrocyte activation is a critical aspect of brain health and disease, and the central circadian clock protein BMAL1 has emerged as a regulator of astrogliosis and inflammatory gene expression. Bmal1 deletion in astrocytes reprograms endolysosomal transcriptional pathways, inducing endocytosis, lysosomal degradation, and autophagic activity. This regulation of proteostasis by BMAL1 implicates circadian clock proteins in neurodegenerative diseases. Studies suggest that astrocyte activation is a complex process with diverse phenotypes beyond classic markers such as GFAP, exhibiting neurotoxic and neuroprotective effects. Deletion of Bmal1 in astrocytes has shown protective effects in models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), influencing Aβ accumulation and α-syn pathology, respectively, through a state of protective astrocyte activation that mitigates tauopathy and α-syn pathology, possibly through the induction of the chaperone protein BAG3. These findings suggest that BMAL1 is crucial in regulating astrocytic function and neuroprotection in neurodegenerative diseases. This review explores the relationship between circadian dysfunction and the development/progression of AD and PD. Furthermore, it recapitulates the most recent findings on manipulating the clock protein BMAL1 and its potential protective effects in astrocytes.

Neuroglia doi: 10.3390/neuroglia5040032

Authors: Ki Jung Kim Rachel E. Patterson Juan Ramiro Diaz Philip O’Herron Weston Bush Ferdinand Althammer Javier E. Stern Michael W. Brands Zsolt Bagi Jessica A. Filosa

Background: Chronic hypoperfusion is a risk factor for neurodegenerative diseases. However, the sequence of events driving ischemia-induced functional changes in a cell-specific manner is unclear. Methods: To address this gap in knowledge, we used the bilateral common carotid artery stenosis (BCAS) mouse model, and evaluated progressive functional changes to neurons, arterioles, astrocytes, and microglial cells at 14 and 28 days post-BCAS surgery. To assess the neuro-glio-vascular response to an acute ischemic insult, brain slices were superfused with low O2 conditions. Using whole-cell patch-clamp electrophysiology, we measured basic membrane properties (e.g., resting membrane potential, capacitance, input resistance) in cortical pyramidal neurons. The activity of astrocytes was evaluated by monitoring Ca2+ from Aldh1l1-CreERT2; R26-lsl-GCaMP6f mice. Vascular reactivity to low O2 from the BCAS mice was also assessed ex vivo. Results: Our data showed no changes to the basic membrane properties of cortical pyramidal neurons. On the other hand, astrocyte activity was characterized by a progressive increase in the resting Ca2+. Notably, at 14 and 28 days post-BCAS, there was an increased expression of anti-inflammatory-related markers (IL-10, S100A10, TRPA1, and Nrf2). These data suggest that, in young mice, BCAS-induced increases in resting Ca2+ were associated with the expression of neuroprotective signals. Contrary to observations in glial cells, vascular function was impaired post-BCAS surgery, as shown by a blunted vasodilatory response to low O2 and the vasodilatory signal, adenosine. Conclusions: Together, these data suggest that, in young mice, BCAS leads to vascular dysfunction (e.g., impaired vasodilation in parenchymal arterioles), and in the absence of neuronal dysfunction, mild ischemia is associated with the activation of glial-derived neuroprotective signals.

Neuroglia doi: 10.3390/neuroglia5040031

Authors: Nawab John Dar Javeed Ahmad Bhat Urmilla John Shahnawaz Ali Bhat

Neurodegenerative diseases represent a significant global health burden, characterized by progressive loss of neuronal function and structure. While traditionally viewed as primarily neuronal disorders, recent research has highlighted the crucial roles of neuroglia-astrocytes, microglia, and oligodendrocytes in the pathogenesis and progression of these diseases. This review explores the dual nature of glial cells in neurodegenerative processes, focusing on their protective and potentially harmful functions in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurodegenerative disorders. We examine the complex interactions between different glial cell types and neurons, highlighting recent discoveries in glial-neuronal metabolic coupling, neuroinflammation, and protein aggregation. Advanced technologies, such as single-cell RNA sequencing and spatial transcriptomics, have revealed unprecedented glial heterogeneity and disease-specific glial states, reshaping our understanding of these cells’ roles in health and disease. The review also discusses emerging concepts in neuroglial research, including the role of extracellular vesicles in disease propagation, epigenetic regulation of glial function, and the application of artificial intelligence in glial biology. Finally, we explore the therapeutic implications of targeting glia in neurodegenerative diseases, addressing both the promising avenues and challenges in developing glial-focused interventions. By integrating recent advances in neuroglial research, this review provides a comprehensive overview of the field and highlights future directions for research and therapeutic development. Understanding the complex roles of neuroglia in neurodegenerative diseases is crucial for developing more effective treatments and ultimately improving patient outcomes.

Neuroglia doi: 10.3390/neuroglia5040030

Authors: Iraís Viveros-Martínez Cristofer Zarate-Calderon Donají Chi-Castañeda Porfirio Carrillo Gonzalo E. Aranda-Abreu Armando J. Martínez Jorge Manzo Genaro A. Coria Luis I. García

Parkinsonism is a clinical syndrome characterized by akinesia/bradykinesia, muscle rigidity, resting tremor, and postural instability. Within the group of parkinsonisms is Parkinson’s disease, also known as neurodegenerative parkinsonian syndrome. The group of atypical parkinsonisms was established due to the existence of sporadic parkinsonisms that do not share the exact etiology of Parkinson’s disease. Additionally, parkinsonisms that arise from causes other than neurodegeneration have been classified as secondary parkinsonisms. With this in mind, given the diversity of etiologies that can trigger parkinsonism, it is crucial to understand the symptomatology and its relationship with the basal ganglia (including damage to the nigrostriatal pathway, neuroinflammation, and neuronal damage). Only then will it be possible to propose appropriate treatments for each variant of parkinsonism.

Neuroglia doi: 10.3390/neuroglia5040029

Authors: Siddharth Shah Hritvik Jain

Background: Neuroinflammation has long been implicated in the progression of amyloid beta (Aβ) accumulation and the decline of cognitive function in Alzheimer’s disease (AD). The phenotype balance between A1 (toxic) and A2 (safe) microglial phenotypes to toxic illness in AD has become a hot research topic at present. Currently, many transcription factors, downstream signaling pathways, and molecular mechanisms that regulate the polarization of microglia are being explored. Furthermore, microglia may also exert a complex role in AD through the transformation of Aβ plaques or debris clearance, reflected in Aβ phagocytosis. One of the mediators of neuroinflammation in AD is the activated microglia. Therefore, the regulation of microglial function may be the key to successfully treating AD. Methods: This paper is a review article. PubMed, Embase, Scopus, and research meeting abstracts were searched up to 2024 for studies of microglia and neuroinflammation in Alzheimer’s Disease. Systematic information retrieval was performed, and appropriate studies were isolated based on important information available in the studies. The information from each of the articles was understood and extracted to form a database. Results: The similar neuropathological results between several animals and AD cases show the possibility of implementing microglia-related changes as an earlier diagnostic marker for AD in humans. The gene sets identified in various transcriptomic studies further foster this avenue of research by offering potential targets for therapeutic development. Substantial evidence, both in vitro and in vivo, has suggested that the loss of the normal A2 phenotype and the activation of toxic A1 microglia contribute to neurodegeneration in AD. Conclusions: Promoting or restoring the polarization of microglia towards the A2 phenotype may thus represent an effective therapeutic strategy for ameliorating neuroinflammation and progressive neurocognitive impairments. Multiple studies suggest that microglia-associated neuroinflammation at a special stage could also be protective, and, therefore, intervention should be delicate so that a beneficial response is retained.

Neuroglia doi: 10.3390/neuroglia5040028

Authors: Robert Logan Sagar Bhatta Hande Eda Sutova Brian P. Hafler Sean J. Miller

Background/Objectives: Wnt signaling pathways are essential in various biological processes, including embryonic development and tissue homeostasis, and are implicated in many diseases. The R-Spondin (RSpo) family, particularly RSpo1, plays a significant role in modulating Wnt signaling. This study aims to explore how RSpo1 binding to astrocytic LGR6 receptors influences central nervous system (CNS) homeostasis, particularly in the context of inflammation. Methods: Human-induced pluripotent stem cell-derived astrocytes were treated with RSpo1 to assess its impact on inflammatory cytokine release. A proteomic analysis was conducted using a Human Cytokine Array Kit to measure differential protein expression. Pathway enrichment analysis was performed to identify affected signaling pathways. Results: RSpo1 treatment led to a suppression of inflammatory cytokines such as IL-10, IFN-γ, and IL-23 in astrocytes, while TNF-α and CXCL12 levels were increased. Pathway analysis revealed significant alterations in key signaling pathways, including cytokine–cytokine receptor interaction, chemokine signaling, and TNF signaling pathways, suggesting RSpo1’s role in modulating immune responses within the CNS. Conclusions: RSpo1 significantly influences inflammatory responses in astrocytes by modulating cytokine release and altering key signaling pathways. These findings enhance our understanding of the interaction between cell-specific Wnt signaling and CNS inflammation, suggesting potential therapeutic applications of RSpo1 in neuroinflammatory and neurodegenerative diseases.

Neuroglia doi: 10.3390/neuroglia5040027

Authors: Al Riyad Hasan Faria Tasnim Md. Aktaruzzaman Md. Tarikul Islam Rifat Rayhan Afrina Brishti Junguk Hur James E. Porter Md. Obayed Raihan

Microglia, the unique and motile immune cells of the central nervous system (CNS), function as a security guard in maintaining CNS homeostasis, primarily through calcium signaling. The calcium dynamics in microglia control important functions such as phagocytosis, cytokine release, and migration. Calcium dysregulation in microglia has been linked to several CNS disorders, like Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke (IS). Calcium entering through channels such as voltage-gated calcium channels (VGCCs), store-operated calcium entry (SOCE), and transient receptor potential (TRP) channels is essential for microglial activation and pro-inflammatory responses. Under pathological conditions, like the formation of amyloid-β plaques in AD, aggregation of α-synuclein in PD, and oxidative stress in MS, calcium dysregulation exacerbates neuroinflammation, mitochondrial dysfunction, and neurodegeneration. Therapeutic strategies targeting calcium signaling pathways, using calcium channel blockers and antioxidant interventions, show promise for alleviating microglial activation and slowing down disease progression. This review summarizes the underlying mechanisms of microglial calcium dysregulation and potential therapeutic benefits for restoring microglial calcium balance in CNS disorders.

Neuroglia doi: 10.3390/neuroglia5040026

Authors: Devlina Ghosh Alok Kumar

Introduction: Mitophagy, the selective degradation of damaged mitochondria, is essential for maintaining cellular health and function, particularly in high-energy demanding post-mitotic cells like neurons and in microglial cells. Aging results in impaired mitophagy, leading to mitochondrial dysfunction, oxidative stress, the release of damage-associated proteins (DAMPs), and neuroinflammation, which contribute to neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Mitochondrial dysfunction also contributes to the pathophysiology of depression by affecting synaptic plasticity, increasing neuroinflammation, and heightening oxidative stress. Aim: In this review, we summarize the recent developments on mechanisms of mitophagy, its therapeutic role in neuroprotection, and its implications in aging and neuroinflammation, complemented by future research requirements and implications. Result/Discussion: Therapeutic strategies that promote mitochondrial health, including enhancing mitophagy and mitochondrial biogenesis, show promise in treating neurodegenerative diseases and depression. Recent findings have emphasized therapeutic strategies to modulate mitophagy, such as pharmacological agents like urolithin A and rapamycin, genetic interventions such as PINK1/Parkin gene therapy, mitochondrial transplantation, and lifestyle and dietary interventions such as caloric restriction, exercise, and dietary supplements such as resveratrol and CoQ10. Key regulators of mitophagy, including the PINK1/Parkin pathway and various proteins like BNIP3, NIX, and FUNDC1, which facilitate the removal of damaged mitochondria, play a crucial role. Conclusions: These results highlight the importance of understanding the interplay between mitophagy and neuroinflammation and show that modulation of mitophagy can reduce oxidative stress and improve neuroinflammatory outcomes and depression in age-related neurodegenerative diseases. However, despite significant progress, challenges remain in understanding the underlying molecular mechanisms of mitophagy and its therapeutic regulation in aging disorders.

Neuroglia doi: 10.3390/neuroglia5040025

Authors: Kajari Bhattacharya Abhishek Mahajan

Central nervous system (CNS) neoplasms are a vast and diverse group of tumors in adults with variable prognoses depending on histology and increasingly understood molecular features. There has been a major paradigm shift in the approach towards these neoplasms ever since the implications of these molecular features have been recognized. Gliomas are the major group of primary CNS neoplasms in adults, and glioblastomas are a significant cause of morbidity and mortality, especially in older patients. Apart from gliomas, meningiomas and pituitary tumors are other major groups. This review aims to elucidate the role of imaging in the screening, diagnosis, management, and follow-up of major primary CNS neoplasms, with an elaborate discussion on the role of artificial intelligence and advanced imaging techniques and future directions likely to play a pivotal role in this ever-evolving subspecialty of oncology.

Neuroglia doi: 10.3390/neuroglia5040024

Authors: Konstantinos Barmpagiannos Nikolaos Lazaridis Aikaterini Apostolopoulou Barbara Fyntanidou

Introduction: Acute brain injury is one of the most important causes of morbidity, mortality and disability worldwide. Time is the most important aspect of acute brain injury management. In this context, biomarkers could mitigate the limitations of neuroimaging. Neuro-biomarkers could be used both to diagnose intracranial pathology and to predict the effectiveness of treatment applications. Aim: The aim of this review is to describe the role of various and specific markers of brain damage with particular emphasis on acute brain injury and stroke. Results/discussion: The diagnostic and prognostic value of modern biomarkers remains relatively questionable, although grouping biomarkers into panels is improving their usefulness. The groups of biomarkers that will be analyzed include astrocytic, axonal, neuronal as well as extracellular biomarkers. Conclusion: Future studies will demonstrate the utility of neuro-biomarkers in the diagnosis, prognosis and therapeutic monitoring of patients with acute brain injury in the intensive care unit.

Neuroglia doi: 10.3390/neuroglia5030023

Authors: Daniel P. Radin Rok Cerne Jeffrey Witkin Arnold Lippa

Ampakines—positive allosteric modulators of AMPA-type glutamate receptors (AMPARs)—are drug candidates that have shown substantial promise in pre-clinical models of various neurodegenerative and neuropsychiatric diseases. Much of the study of ampakines has focused on how these drugs modulate neuronal AMPARs to achieve certain therapeutic effects. However, astrocytes also express functional AMPARs and their physiology may be sensitive to modulation by ampakines. Herein, we investigate the effects of multiple ampakines on calcium levels in cortical astrocytes. We find that ampakines augment cytosolic calcium elevations in astrocytes to an extent far greater than that achieved by AMPA alone. This effect is amenable to competitive AMPAR blockade. Furthermore, calcium induction is sensitive to phospholipase Cβ antagonism and blockade of inositol triphosphate receptors located on the endoplasmic reticulum. Low-impact ampakines exerted weaker effects on cytosolic calcium levels in astrocytes and higher concentrations were required to observe an effect. Furthermore, high doses of the low-impact ampakine, CX717, were not toxic to cortical astrocytes at high concentrations, which may serve to differentiate low-impact ampakines from classical AMPAR positive modulators like cyclothiazide. As ampakines are further developed for clinical use, it would be prudent to determine the extent to and manner by which they affect astrocytes, as these effects may also underpin their therapeutic utility in CNS pathologies.

Neuroglia doi: 10.3390/neuroglia5030022

Authors: Roger M. Lane Dan Li Taher Darreh-Shori

Background: This study examined the impact of apolipoprotein ɛ4 (APOEɛ4) allele frequency and sex on the phenotype of Alzheimer’s disease (AD). Methods: This post hoc study evaluated the baseline characteristics, cerebrospinal fluid (CSF) and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50–74 years with CSF-biomarker-confirmed mild cognitive impairment or mild dementia due to AD from clinical trial NCT03186989. Results: A phenotypic spectrum was observed from a predominant amyloid and limbic–amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology was inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest associations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers. Conclusions: These data support the hypothesis that functional glial activation is influenced by apoE isoform and sex and might explain much of the biological and clinical heterogeneity in early clinical AD in those aged 50–74 years. Conclusions are limited because of the retrospective nature and small sample size. Trial Registration: Clinical Trial NCT03186989.

Neuroglia doi: 10.3390/neuroglia5030021

Authors: Ajay Sarawagi Pratishtha Wadnerkar Vrundika Keluskar Narra Sai Ram Jerald Mahesh Kumar Anant Bahadur Patel

Electroconvulsive therapy (ECT) is an effective treatment for severe and drug-resistant depression, yet its mode of action remains poorly understood. This study aimed to evaluate the effects of ECT on neurometabolism using ex vivo 1H-[13C]-NMR spectroscopy in conjunction with intravenous infusion of [1,6-13C2]glucose in a chronic variable mild stress (CVMS) model of depression. Both CVMS and control mice were subjected to seven sessions of electroconvulsive shock under mild isoflurane anesthesia. The CVMS mice exhibited a reduction in sucrose preference (CVMS 67.1 ± 14.9%, n = 5; CON 86.5 ± 0.6%, n = 5; p = 0.007), and an increase in immobility duration (175.9 ± 22.6 vs. 92.0 ± 23.0 s, p < 0.001) in the forced-swim test. The cerebral metabolic rates of glucose oxidation in glutamatergic (CMRGlc(Glu)) (CVMS 0.134 ± 0.015 µmol/g/min, n = 5; CON 0.201 ± 0.045 µmol/g/min, n = 5; padj = 0.04) and GABAergic neurons (CMRGlc(GABA)) (0.030 ± 0.002 vs. 0.046 ± 0.011 µmol/g/min, padj = 0.04) were reduced in the prefrontal cortex (PFC) of CVMS mice. ECT treatment in CVMS mice normalized sucrose preference [F(1,27) = 0.0024, p = 0.961] and immobility duration [F(1,28) = 0.434, p = 0.515], but not the time spent in the center zone (CVMS + ECT 10.4 ± 5.5 s, CON + sham 22.3 ± 11.4 s, padj = 0.0006) in the open field test. The ECT-treated CVMS mice exhibited reduced (padj = 0.021) CMRGlc(Glu) in PFC (0.169 ± 0.026 µmol/g/min, n = 8) when compared with CVMS mice, which underwent the sham procedure (0.226 ± 0.030 µmol/g/min, n = 8). These observations are consistent with ECT’s anticonvulsant hypothesis for its anti-depressive action.

Neuroglia doi: 10.3390/neuroglia5030020

Authors: Hassan E. Mohammed James C. Nelson S. Alex Marshall

Alzheimer’s disease (AD) is the most common form of dementia with characteristic biological markers. Clinically, AD presents as declines in memory, reasoning, and decision making, but the loss of memory is particularly associated with hippocampal damage. Likewise, excessive ethanol consumption has been found to disrupt hippocampal function and integrity. To assess the potential shared consequences of AD pathology and ethanol, 5xFAD mice were administered 5 g/kg ethanol daily for 10 days. Immunohistochemical analysis revealed ethanol and AD converged to lead to microglial and astrocytic senescence as well as increased Aß-plaque formation in the hippocampus. Despite the exacerbation of these potential mechanisms of neurodegeneration, there were no additive effects of ethanol exposure and AD-related genotype on Fluoro-Jade C (FJC)+ cells or cognitive deficits in the novel object recognition task. Overall, these results are the first to characterize the effects of ethanol exposure on early adulthood in the 5xFAD mouse model. Together these findings support the idea that alcohol can influence AD pathology; however, the mechanisms involved in AD progression (e.g., glial activation and Aß-plaque) may be impacted prior to evidence of pathology (e.g., cognitive decline or neuronal loss).

Neuroglia doi: 10.3390/neuroglia5030019

Authors: Natalie K. Thomaz Larissa Daniele Bobermin André Quincozes-Santos

Sexual dimorphism refers to biological differences between males and females in the same species, including morphological, physiological, and behavioral characteristics. Steroid hormones are associated with changes in several brain regions, as well as the pathophysiology of aging, obesity, and neuropsychiatric diseases. The hypothalamus controls several physiological processes, including metabolism, reproduction, circadian rhythm, and body homeostasis. Refined communication between neurons and glial cells, particularly astrocytes, coordinates physiological and behavioral hypothalamic functions. Therefore, from previously published studies, this review aims to highlight sex-related differences in rodent hypothalamic astrocytes, since we believe that this brain region is essential for the understanding of dimorphic patterns that are influenced by steroid sex hormones. Thus, we review concepts of sexual dimorphism, the hypothalamic-pituitary-gonadal axis, the role of hormonal influence on hypothalamic astrocyte functions, neuroglial communication, as well as sexual dimorphism and neuropsychiatric disorders and glioprotective mechanisms associated with the hypothalamus.

Neuroglia doi: 10.3390/neuroglia5030018

Authors: Josué Camberos-Barraza Alma M. Guadrón-Llanos Alberto K. De la Herrán-Arita

The human central nervous system is convolutedly connected to the gut microbiome, a diverse community of microorganisms residing in the gastrointestinal tract. Recent research has highlighted the bidirectional communication between the gut microbiome and neuroglial cells, which include astrocytes, microglia, oligodendrocytes, and ependymal cells. These neuroglial cells are essential for maintaining CNS homeostasis, supporting neuronal function, and responding to pathological conditions. This review examines the interactions between the gut microbiome and neuroglia, emphasizing their critical roles in brain health and the development of neurological disorders. Dysbiosis, or imbalance in the gut microbiome, has been associated with various neurological and psychiatric conditions, such as autism spectrum disorder, anxiety, depression, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. The microbiome influences brain function through microbial metabolites, immune modulation, and neuroinflammatory responses. Understanding these interactions paves the way for new therapeutic targets and strategies for preventing and treating CNS disorders. This scoping review aims to highlight the mechanisms of the microbiome-neuroglia axis in maintaining brain health and its potential as a therapeutic target.

Neuroglia doi: 10.3390/neuroglia5030017

Authors: Akanksha Jha Hemant Kumar

Microglia are poorly understood immune cells of the central nervous system that play a determining role in the progression of multiple sclerosis. With the advent of genomic techniques such as single-cell RNA sequencing and single-nucleus RNA sequencing, a more comprehensive understanding of microglia at the transcriptomic level has uncovered various disease-specific clusters, context-dependent heterogeneity, and region-specific microglia, unlocking the recondite secrets embedded within these glial cells. These techniques have raised questions regarding the conventional and widely accepted categorization of microglia as M1 and M2 phenotypes. The neuroimmune component of multiple sclerosis, which is the microglia, makes it a complex and challenging disease. This review aims to demystify the complexities of microglia in multiple sclerosis, providing a vivid map of different clusters and subclusters of microglia found in multiple sclerosis and outlining the current knowledge of the distinctive roles of microglia. Also, this review highlights the neuroimmune interaction with microglia as the epicenter and how they act as sabotaging agents. Moreover, this will provide a more comprehensive direction toward a treatment approach focusing on local, region-specific microglia.

Neuroglia doi: 10.3390/neuroglia5030016

Authors: Richard E. Kast

Glioblastomas synthesize, bear receptors for, and respond to bradykinin, triggering migration and proliferation. Since centrifugal migration into uninvolved surrounding brain tissue occurs early in the course of glioblastoma, this attribute defeats local treatment attempts and is the primary reason current treatments almost always fail. Stopping bradykinin-triggered migration would be a step closer to control of this disease. The recent approval and marketing of an oral plasma kallikrein inhibitor, berotralstat (Orladeyo™), and pending FDA approval of a similar drug, sebetralstat, now offers a potential method for reducing local bradykinin production at sites of bradykinin-mediated glioblastoma migration. Both drugs are approved for treating hereditary angioedema. They are ideal for repurposing as a treatment adjunct in glioblastoma. Furthermore, it has been established that peritumoral edema, a common problem during the clinical course of glioblastoma, is generated in large part by locally produced bradykinin via kallikrein action. Both brain edema and the consequent use of corticosteroids both shorten survival in glioblastoma. Therefore, by (i) migration inhibition, (ii) growth inhibition, (iii) edema reduction, and (iv) the potential for less use of corticosteroids, berotralstat may be of service in treatment of glioblastoma, slowing disease progression. This paper recounts the details and past research on bradykinin in glioblastoma and the rationale of treating it with berotralstat.

Neuroglia doi: 10.3390/neuroglia5030015

Authors: Vanir Reis Pinto-Junior Rodrigo Lopes Seeger Cláudio Henrique Dahne Souza-Filho Angela Patricia França Nicole Sartori Messias Vital Oliveira Vinicius Jose Silva Osterne Kyria Santiago Nascimento Rodrigo Bainy Leal Benildo Sousa Cavada

Studies have revealed the dependence of glioma cells on iron, making them sensitive to ferroptosis. Ferroptosis can be triggered by inhibition of the xc- system, resulting in redox imbalance and membrane lipid peroxidation. The xc- system is composed of two coupled proteins, xCT and CD98hc. The control of transporters, such as xCT, by the CD98hc glycoprotein suggests that molecules targeting glycans may have an impact on the treatment of glioma. This study evaluated the effect of the Canavalia brasiliensis (ConBr) lectin on C6 glioma cells and compared it with erastin, an xc- system inhibitor. Both induced dose-dependent cell death, accompanied by an increase in the production of reactive oxygen species and a decrease in reduced glutathione. However, co-treatment did not show an additive effect. The analysis was updated by molecular dynamics assessments of the xc- system interacting with ConBr or erastin. The interaction of erastin with the xc- system affects its interaction with ConBr, reducing the antagonistic effect when both are in the protein complex. The data show that ConBr is effective in inducing cell death in glioma cells and regulates the xc system through interaction with CD98hc glycans, showing that lectins have the potential to promote ferroptosis in glioma cells.

Neuroglia doi: 10.3390/neuroglia5020014

Authors: Kwame O. Affram Zachary C. Janatpour Nagesh Shanbhag Sonia Villapol Aviva J. Symes

Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting microglial activation could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects in the brain and are considered potential therapies for neurodegenerative diseases and neurotrauma. Although all ARBs are angiotensin II receptor type I antagonists, some ARBs act through other signaling pathways, allowing for multiple mechanisms of action. The anti-inflammatory mechanisms of ARBs are not well understood. Methods: In this study, we compared eight different FDA-approved ARBs for their ability to reduce the LPS stimulation of primary microglia or BV2 cells through analyses of nitric oxide production, reactive oxygen species generation, and the mRNA of proinflammatory cytokines. Finding specific and unique effects of telmisartan, we interrogated signaling pathways and other downstream effectors of telmisartan activity on microglia. Results: Our findings indicate that telmisartan showed the greatest efficacy in reducing the LPS induction of reactive oxygen species (ROS) and nitric oxide production in microglia. Uniquely amongst ARBs, telmisartan activated AMPK phosphorylation and inhibited mTOR phosphorylation. Telmisartan’s anti-inflammatory activity was partially inhibited by the AMPK inhibitor compound C. Furthermore, telmisartan uniquely induced markers of autophagy in microglia through an AMPK–mTOR–autophagy pathway. Telmisartan also reduced microglial viability. Telmisartan’s cytotoxicity was partially ameliorated by an autophagy inhibitor and a pan-caspase inhibitor, indicating a link between microglial autophagy and apoptosis. Conclusions: We conclude that telmisartan has unique properties relative to other ARBs, including potent anti-inflammatory actions and an induction of microglial autophagy, which may enable specific therapeutic uses.

Neuroglia doi: 10.3390/neuroglia5020013

Authors: Antonello Curcio Shervin Espahbodinea Eva Azzurra Li Trenta Rosamaria Ferrarotto Aristide Nanni Noemi Arabia Giorgio Ciccolo Giovanni Raffa Francesca Granata Antonino Germanò

Background: Angiocentric glioma (AG) is a rare, benign, and slow-growing tumor. First described in 2005, it is now gaining attention with respect to the possibility of being diagnosed. Even with no statistical differences between sex, it has been reported both in children and the elderly. A total of 120 cases have been described in the literature. The aim of this study is to provide new data for a new statistical assessment of the prevalence and incidence of AG in populations. Case report: An 8-year-old male patient with no history of epilepsy and no need for antiepileptic therapy underwent surgery for a left-parietal brain lesion, revealed through MRI. Imaging was acquired after his first absence episode. The lesion was completely resected. Histological findings indicated angiocentric glioma. No signs of recurrency after two years of follow-up. Conclusion: AG is usually an epilepsy-related low-grade glioma. Few cases exhibit disease progression and exitus. Surgical management should aim for a gross total resection to avoid recurrence and persisting epilepsy. Surgery represents the gold standard in diagnosis and treatment and must be performed as soon as possible in consideration of its healing properties and its useful diagnosis.

Neuroglia doi: 10.3390/neuroglia5020012

Authors: JuliAnne Allgood Avery Roe Jessica E. Pullan

The current lack of a comprehensive understanding of brain metastasis mechanisms presents a significant gap in cancer research. This review outlines the role that Schwann cells (SCs) have in this process. SCs are already known for their role in myelination and nerve repair within the peripheral nervous system (PNS), but there is less information on their function in facilitating the transport and activation of neoplastic cells to aid in the invasion of the blood–brain barrier and brain. Detailed insights into SCs’ interactions with various cancers, including lung, breast, melanoma, colon, kidney, and pancreatic cancers, reveal how these cells are coerced into repair-like phenotypes to accelerate cancer spread and modulate immune responses. By outlining SCs’ involvement in perineural invasion and BBB modification, this review highlights their functions in facilitating brain metastasis.

Neuroglia doi: 10.3390/neuroglia5020011

Authors: Guillaume Mestrallet

Glioma, a highly aggressive cancer, presents a daunting prognosis, with only 5% of glioblastoma patients surviving beyond five years post diagnosis. Current therapeutic strategies, including surgical intervention, radiotherapy, chemotherapy, and immune checkpoint blockade (ICB), while promising, often encounter limited efficacy, particularly in glioblastoma cases. Addressing this challenge requires a proactive approach to anticipate treatment response and resistance. In this study, we analyzed 117 glioma patients who underwent ICB treatment to uncover the mechanisms underlying treatment resistance. Through a meticulous examination of mutational profiles post ICB, we identified several mutations associated with varied survival outcomes. Notably, mutations such as STAG2 Missense, EGFR A289V Missense, TP53 Nonsense, and RB1 FS del were linked to prolonged overall survival, while others, including IF del, FAT1 E1206Tfs*4 FS del, PDGFRA FS del, PIK3R1 M326Vfs*6 FS del, Y463* Nonsense, NF1 Missense, and R1534*, were associated with poorer survival post ICB. Leveraging these insights, we employed machine learning algorithms to develop predictive models. Remarkably, our model accurately forecasted glioma patient survival post ICB within an error of 4 months based on their distinct mutational profiles. In conclusion, our study advocates for personalized immunotherapy approaches in glioma patients. By integrating patient-specific attributes and computational predictions, we present a promising avenue for optimizing clinical outcomes in immunotherapy.