Neuroglia

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. Full article

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 C_β 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. Full article

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. Full article

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 (CMR_Glc(Glu)) (CVMS 0.134 ± 0.015 µmol/g/min, n = 5; CON 0.201 ± 0.045 µmol/g/min, n = 5; p_adj = 0.04) and GABAergic neurons (CMR_Glc(GABA)) (0.030 ± 0.002 vs. 0.046 ± 0.011 µmol/g/min, p_adj = 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, p_adj = 0.0006) in the open field test. The ECT-treated CVMS mice exhibited reduced (p_adj = 0.021) CMR_Glc(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. Full article

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). Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Several protocols have been developed with the aim of characterizing glial and immune cells from the central and peripheral nervous systems. However, a small number of these protocols have demonstrated the ability to yield satisfactory results following conventional isolation. Considering this necessity and the difficulties encountered in enzymatic and bead isolation, our work proposes a method for the isolation of glial and immune cells from the spinal cord utilizing a Percoll gradient. For this purpose, C57BL/6J spinal cords were dissected, and the lumbar intumescence was dissociated and subjected to a Percoll gradient centrifugation (70%, 50%, 37%, and 10%). Each layer was then separated and labeled for astrocytes (anti-GFAP, TNF-α, IFN-γ, IL-10, IL-4), microglia (anti-CD45, CD11b, CD206, CD68, TNF-α, IFN-γ), and lymphocytes (anti-CD3, CD4, IFN-γ, IL-4). The gate detections were mathematically performed by computational analysis utilizing the K-means clustering algorithm. The results demonstrated that astrocytes were concentrated at the Percoll 10/37 interface, microglia at the Percoll 37/50 layer, and lymphocytes at the Percoll 50/70 layer. Our findings indicate that astrocytes in healthy animals are putative of the A1 profile, while microglia and lymphocytes are more frequently labeled with M1 and Th1 markers, suggesting a propensity towards inflammatory responses. The computational method enabled the semi-autonomous gate detection of flow cytometry data, which might facilitate and expedite the processing of large amounts of data. Full article

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are clinically distinct, yet share synaptic dysfunction as a common brain pathophysiology. Neurodegenerative diseases such as Huntington’s disease (HD) entail a neuroinflammatory cascade of molecular and cellular events which can contribute to the death of neurons. Emerging roles for supportive glial cells such as microglia and astrocytes in the ongoing regulation of neural synapses and brain excitability raise the possibility that some of the synaptic pathology and/or inflammatory events could be a direct consequence of malfunctioning glial cells. Focusing on microglia, we cross-examined 12 recently published studies in which microglial dysfunction was induced/identified in a cell-autonomous manner and its functional consequence on neural development, brain volume, functional connectivity, inflammatory response and synaptic regulation were evaluated; in many cases, the onset of symptoms relevant to all three neurodevelopmental disorders were assessed behaviorally. Challenging the classic notion of microglial activation as an inflammatory response to neuropathology, our compilation clarifies that microglial dyshomeostasis itself can consequently disrupt neural homeostasis, leading to neuropathology and symptom onset. This further warranted defining the molecular signatures of context-specific microglial pathology relevant to human diseases. Full article

Brain tumors necessitate swift detection and classification for optimal patient outcomes. Deep learning has been extensively utilized to recognize complex tumor patterns in magnetic resonance imaging (MRI) images, aiding in tumor diagnosis, treatment, and prognostication. However, model complexity and limited generalizability with unfamiliar data hinder appropriate clinical integration. The objective of this study is to develop a clean-energy cloud-based deep learning platform to classify brain tumors. Three datasets of a total of 2611 axial MRI images were used to train our multi-layer convolutional neural network (CNN). Our platform automatically optimized every transfer learning and data augmentation feature combination to provide the highest predictive accuracy for our classification task. Our proposed system identified and classified brain tumors successfully and efficiently with an overall precision value of 96.8% [95% CI; 93.8–97.6]. Using clean energy supercomputing resources and cloud platforms cut our workflow to 103 min, $0 in total cost, and a negligible carbon footprint (0.0014 kg eq CO₂). By leveraging automated optimized learning, we developed a cost-effective deep learning (DL) platform that accurately classified brain tumors from axial MRI images of different levels. Although studies have identified machine learning tools to overcome these obstacles, only some are cost-effective, generalizable, and usable regardless of experience. Full article

The traditional neuron-centric view of the central nervous system (CNS) is shifting toward recognizing the importance of communication between the neurons and the network of glial cells. This shift is leading to a more comprehensive understanding of how glial cells contribute to CNS function. Alongside this shift, recent discoveries have illuminated the significant role of the human microbiome, comprising trillions of microorganisms, mirroring the number of human cells in an individual. This paper delves into the multifaceted functions of neuroglia, or glial cells, which extend far beyond their traditional roles of supporting and protecting neurons. Neuroglia modulate synaptic activity, insulate axons, support neurogenesis and synaptic plasticity, respond to injury and inflammation, and engage in phagocytosis. Meanwhile, the microbiome, long overlooked, emerges as a crucial player in brain functionality akin to glial cells. This review aims to underscore the importance of the interaction between glial cells and resident microorganisms in shaping the development and function of the human brain, a concept that has been less studied. Through a comprehensive examination of existing literature, we discuss the mechanisms by which glial cells interface with the microbiome, offering insights into the contribution of this relationship to neural homeostasis and health. Furthermore, we discuss the implications of dysbiosis within this interaction, highlighting its potential contribution to neurological disorders and paving the way for novel therapeutic interventions targeting both glial cells and the microbiome. Full article

Glioblastoma (GBM) is the predominant primary malignant brain tumor. Metformin, a well-known antidiabetic medication, has emerged as a potential therapeutic candidate in the treatment of GBM. We have herein investigated two aspects of the effect of MTF on GBM cells: the effect of MTF on GBM cell viability, as previous studies have shown that MTF can selectively affect human GBM tumors; and the immunomodulatory effect of MTF on GBM, as there is evidence that inflammation is associated with GBM growth and progression. The human GBM cell line (U87) was exposed to various doses of MTF (1 mM, 20 mM, and 50 mM), followed by examination of cell viability and inflammatory mediator secretion at various time points. We observed that MTF treatment exerted a dose-response effect on glioblastoma multiforme cell viability. It also had an immunomodulatory effect on GBM cells. Our study identified several mechanisms that led to the overall inhibitory effect of MTF on human GBM. Further inquiry is necessary to gain a better understanding of how these in vitro findings would translate into successful in vivo approaches. Full article