Search Results (3,156)

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine–neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine–BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders. Full article

Background/Objectives: Phthalates are a group of organic compounds widely used for enhancement in flexibility and transparency of polyvinyl chloride (PVC) products. Exposure to phthalate-containing substances has been shown to affect brain function, particularly in learning and memory processes. Quercetin is a plant-derived flavonoid with remarkable anti-oxidant and anti-inflammatory potential. This study investigated the possible protective effects of quercetin on spatial learning and memory, histomorphometric changes, and hippocampal expression of inflammatory cytokines (TNF-α and IL-6) in male mice exposed to di(2-ethylhexyl) phthalate (DEHP). Methods: A total of 42 male mice were divided into seven groups. Quercetin was administered orally at doses of 25 and 50 mg/kg/day, either alone or in combination with DEHP (200 mg/kg/day). Following the final day of the treatment, spatial learning and memory were assessed by the Morris Water Maze test. Hippocampal tissues were sampled for Nissl, H&E, and immunofluorescence staining. Quantitative real-time PCR was used to measure the expression of TNF-α and IL-6. Results: The DEHP group exhibited significant impairments in learning and memory, neuronal damage, and cellular disorganization in the hippocampus, along with increased astrocyte activation and elevated expression of TNF-α and IL-6. On the other hand, quercetin supplementation significantly reduced these inflammatory markers and histological damages and also improved spatial learning and memory. Conclusions: Overall, quercetin improves cognitive function that is associated with attenuating astrocyte activation and inflammation. Full article

Glial cells, particularly astrocytes and microglia, are central to maintaining CNS homeostasis and coordinating responses to injury through tightly regulated metabolic, inflammatory, and mechanosensitive processes. Emerging evidence identifies the Hippo signaling pathway and its downstream effectors YAP/TAZ as key regulators of glial functions, influencing proliferation, polarization, intercellular communication, and the balance between neuroprotection and neurotoxicity. This review discusses the Hippo signaling pathway and its transcriptional co-activators YAP/TAZ as context-dependent hubs integrating mechanical, metabolic, and immune cues in astrocytes and microglia. Particular attention is given to MST1/2- and YAP/TAZ-dependent signaling in microglia, which governs inflammatory states, redox balance, mitophagy, and mechanosensing. In astrocytes, Hippo–YAP signaling emerges as a bidirectional regulator of reactive gliosis and neuroprotection, capable of constraining excessive scar formation. However, when chronically suppressed, it impairs glutamate clearance, metabolic support, and resistance to neurodegeneration. Disruption of Hippo signaling in glial tumors is also considered, with YAP/TAZ–TEAD complexes driving glioblastoma stemness, infiltrative growth, immune evasion, and therapy resistance. Finally, therapeutic perspectives are outlined that emphasize context-selective modulation of Hippo signaling in the CNS. Overall, Hippo–YAP/TAZ signaling is presented as a highly context-dependent regulator at the interface of glial inflammation, neurodegeneration, and glioma biology and as a promising but demanding target for future CNS therapies. Full article

Advanced Glycation End Products (AGEs) are reactive compounds formed through the non-enzymatic glycation of proteins, lipids, or nucleic acids due to exposure to reducing sugars. They accumulate through endogenous metabolic dysregulation and exogenous dietary intake, particularly high-fat and high-sugar foods prepared at high temperatures. The interaction between AGEs and their receptor, RAGE (receptor for Advanced Glycation End Products), has been implicated in a range of pathological conditions, including diabetes and metabolic syndrome. However, the impact of AGEs accumulation on neurodevelopment remains poorly understood. In this study, we investigated the effects of AGEs on human-induced pluripotent stem cell (iPSC)-derived cerebral organoids comprising neurons, astrocytes, and microglia. Our findings reveal that AGEs induce RAGE expression, leading to microglial activation, increased deposition of amyloid-beta (Aβ) aggregates, and impaired neurodevelopment. Additionally, elevated levels of AGE-modified proteins, along with altered microglial polarization, were observed in cerebral organoids modeling Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism–Dementia Complex (ALS-PDC). These findings demonstrate AGEs as active drivers of neurodevelopmental disruption and establish a mechanistic link between metabolic stress and increased susceptibility to neurodegenerative disease. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein(REB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

Neuroinflammation mediated by astrocyte–microglia interactions plays a critical role in the progression of neurodegenerative disorders. Celastrus paniculatus (CP) seeds have long been associated with cognitive benefits; however, the chemical composition and anti-inflammatory potential of their high-polarity fractions remain poorly characterized. In this study, thin-layer chromatography (TLC)-derived high-polarity fractions (F6 and F7) from CP seeds were analyzed using untargeted LC–MS/MS metabolite profiling. After quality filtering, 99 metabolites were retained for classification, with enrichment of alkaloids and terpenoid-related compounds, including 41 structurally complex metabolites. To evaluate biological relevance, BV2 microglia were exposed to astrocyte-conditioned medium derived from H₂O₂-treated astrocytes (ACM-H), modeling sterile inflammatory signaling. ACM-H stimulation induced microglial activation characterized by morphological transformation, increased CD40 and inducible nitric oxide synthase (iNOS) expression, and elevated production of pro-inflammatory cytokines TNF-α and IL-6. Co-treatment with CP fractions attenuated ACM-H-induced inflammatory responses, with fraction F7 showing stronger effects than F6. Fraction F7 showed stronger inhibitory effects on CD40 and iNOS expression, suppressed TNF-α and IL-6 production, and partially restored ramified microglial morphology, whereas F6 exhibited comparable anti-inflammatory activity and showed a stronger effect on microglial phagocytic responses. Metabolomic analysis further indicated a higher relative abundance of terpenoid-related metabolites in F7. Collectively, these findings indicate that CP seed fractions, particularly F7, attenuate astrocyte-driven microglial activation in an in vitro sterile neuroinflammatory model. Full article

Neuroimplants represent an emerging medical technology, offering new therapeutic approaches for severe neurological and psychiatric disorders. One of the key limitations to long-term neuroimplant performance is the foreign body response elicited by intracortical implantation. Among the contributing cell types, astrocytes play a central role in glial scar formation around the implant, which can compromise device functionality. Immunofluorescence of glial fibrillary acidic protein (GFAP) provides a well-established marker of astrogliosis (neuroinflammation), yet quantitative and reproducible assessment of astrocyte morphology remains challenging due to the complexity and variability of image analysis approaches. Here, we aimed to quantitatively assess implantation-induced astrogliosis and to determine how classifier training strategy influences segmentation outcomes and morphometric measurements. We present a machine learning-assisted pipeline based on the LabKit plugin in Fiji for segmentation and morphometric analysis of GFAP-positive astrocytes in peri-implant scar versus distant cortical regions. Using this approach, we demonstrate an increase in GFAP expression, cell area, and astrocytic process length as well as the redistribution of GFAP signal along astrocytic processes within scar regions. We show that different classifier training strategies produce systematically distinct segmentation outcomes, with rule-compliant annotation improving agreement with manually defined ground truth. These findings highlight the critical role of annotation strategy in shallow learning-based segmentation and provide a practical framework for improving reproducibility of astrocyte morphometry in studies of neuroinflammation and neuroimplant biocompatibility. Full article

Amygdala dysfunction is implicated in stress-related affective disorders, and astrocytes are key regulators of amygdalar neuroplasticity. Here, we examined whether running exercise modulates astrocyte number, morphology, proliferation, and excitatory synaptic contacts in the basolateral amygdala (BLA) and central amygdala (CeA) in rats exposed to chronic unpredictable stress (CUS). Anhedonia-like behaviors were evaluated using the sucrose preference test, while anxiety-related behaviors were assessed using the elevated plus maze and open field tests. Unbiased stereological three-dimensional quantification was used to assess amygdalar volume and estimate astrocyte numbers in BLA and CeA, and immunofluorescence with morphological reconstruction was performed to quantify astrocytic complexity, proliferation, and astrocyte-associated PSD95⁺ puncta. Running exercise significantly increased sucrose preference in CUS rats, whereas elevated plus maze and open field measures were not significantly changed. CUS reduced astrocyte number and proliferation, and induced astrocytic morphological atrophy in both subregions. These alterations were reversed by running. Moreover, running increased the number of excitatory synapses contacted by astrocytes in the BLA and CeA of CUS rats. These findings suggest that running promotes astrocyte-mediated structural remodeling in amygdalar subregions, which may contribute to the regulation of anhedonia-like behavioral alterations associated with chronic stress. Full article

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by persistent pelvic pain, urinary symptoms, and significant impact on quality of life. In addition to its clinical symptoms, CP/CPPS is frequently associated with psychiatric comorbidities, such as anxiety and depression, indicating complex neurobiological mechanisms. This review explores the mechanisms linking CP/CPPS with affective disorders, emphasizing central nervous system alterations, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and neuroimmune interactions. Evidence in-dicates that central sensitization, microglial and astrocytic activation, and elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) contribute to maladaptive painemotion network interactions. Additionally, dysregulation of hormones and neurotransmitters may exacerbate both pain perception and mood disorders. Psychosocial factors, including stress, coping strategies, and cognitive-emotional processes, further modulate symptom severity and treatment outcomes, highlighting the importance of a biopsychosocial approach. Gaining a deeper understanding of the neurobiological and psychosocial mechanisms behind anxiety and depression in CP/CPPS can lead to more effective, multidimensional management strategies and enhance patient-centered care. Full article

Although LRRK2 mutations modulate systemic glucose homeostasis and metabolic dysfunction precedes Parkinson’s disease (PD) motor symptoms; the way in which pathogenic variants of LRRK2 disrupt astrocytic glucose metabolism and organellar homeostasis remains poorly understood. Here, we demonstrate that LRRK2-I1371V mutation causes profound metabolic and organellar dysfunction in LRRK2-I1371V PD-iPSC-derived astrocytes and U87 cells overexpressing I1371V variant. LRRK2-I1371V astrocytes exhibit significantly reduced GLUT1 expression and cell surface localization, resulting in impaired glucose uptake and decreased lactate production. This metabolic insufficiency correlates with cascading mitochondrial dysfunction, characterized by membrane depolarization, elevated reactive oxygen species, enhanced ubiquitination and reduced proteasomal activity. Reduced LAMP1/LAMP2 expression, impaired lysosomal acidification, and selective cathepsin D deficiency were observed. Accumulation of undegraded cargo was confirmed by transmission electron microscopy upon α-synuclein exposure. ER stress was evident by upregulation of GADD34/CHOP, increased phospho-PERK, and reduced nascent protein synthesis. Increased ER–mitochondrial contact via MAMs and enhanced STIM1-ORAI3 clustering reflect compensatory but ultimately insufficient responses to energy stress. Our results reveal that LRRK2-I1371V induces glucose uptake deficits, leading to energy depletion and integrated ER–mitochondria–lysosome dysfunction, thus indicating restoration of astrocytic metabolic capacity as a potential therapeutic strategy for LRRK2-associated PD. Full article

Cellular senescence represents a critical biological paradox in oncology. Although it evolved as a safety mechanism to halt tumorigenesis through stable cell cycle arrest, its persistence in tissues can alter the microenvironment, promoting tumor recurrence. In the context of glioblastoma (GBM), this phenomenon is critically important, as current standard therapies, such as radiotherapy and chemotherapy, inadvertently induce a state of senescence known as “therapy-induced senescence” (TIS). Senescent cells remain metabolically active and acquire a unique Senescence-Associated Secretory Phenotype (SASP), characterized by the release of pro-inflammatory cytokines, proteases, and growth factors. SASP reshapes the tumor microenvironment (TME) through paracrine signals, promoting immunosuppression, invasiveness, drug resistance and tumor recurrence. Different glial populations, including astrocytes, microglia, and oligodendrocyte precursor cells (OPCs), respond differently to senescence, specifically contributing to the creation of a permissive niche for tumor recurrence. To contrast the effects of this phenomenon, a promising therapeutic strategy has emerged, the “one-two punch,” which induces initial DNA damage followed by selective elimination of senescent cells with senolytic drugs. In this review, we analyze in detail the efficacy of targeted synthetic agents, such as the Bcl-2 family inhibitor Navitoclax, and natural bioactive compounds such as Quercetin and Fisetin. The analysis focuses on the molecular mechanisms through which these agents disrupt anti-apoptotic pathways (SCAPs) and inhibit the PI3K/AKT/mTOR axis, restoring sensitivity to apoptosis. We propose that the integration of senolytic adjuvants into standard clinical protocols may represent a crucial frontier for eliminating residual disease reservoirs and we also suggest the possibility of combining them with molecules with neuroprotective action to significantly improve the prognosis in GBM. Full article

Background: The aim of this study is to investigate the relationship between the expression levels of autophagy-related genes (SQSTM1, Beclin1, Atg5, and Atg7) in diffuse astrocytic tumors and clinicopathological parameters, including tumor grade, IDH mutation status, and survival outcomes. Materials and Methods: A total of 150 histopathologically confirmed diffuse astrocytic tumor cases were retrospectively analyzed. Clinical data were extracted from patient records. Gene expression levels were determined using qRT-PCR and evaluated by the 2^−ΔCt method, where lower ΔCt values indicate higher gene expression. IDH1 R132H mutation status was evaluated by immunohistochemistry. Results: No statistically significant differences were observed in the expression levels of SQSTM1, Beclin1, Atg5, and Atg7 across WHO tumor grades (p > 0.05). However, when analyzed by IDH status, IDH-mutant tumors exhibited significantly higher gene expression levels (demonstrated by lower ΔCt values) of Beclin1 (p = 0.046) and Atg5 (p = 0.027) compared to IDH wild-type tumors. In multivariate Cox regression analysis, age and WHO tumor grades were confirmed as independent prognostic factors. Crucially, higher SQSTM1 expression independently predicted worse clinical outcomes, specifically poorer overall survival (OS) (p = 0.004) and shorter progression-free survival (PFS) (p = 0.031). Additionally, elevated Beclin1 expression was identified as an independent predictor of worse OS (p = 0.023). Conclusions: This study demonstrates that increased expression of autophagy-related genes, particularly SQSTM1 and Beclin1, serves as a robust indicator of poor prognosis and shorter survival times in diffuse astrocytic tumors. Furthermore, the elevated expression of Beclin1 and Atg5 in IDH-mutant cases highlights a complex metabolic interplay that warrants further investigation as potential therapeutic targets. Full article

Fetal hypoxia and maternal stress during pregnancy are major risk factors for neurological disorders. The effects of maternal hypoxia may be transmitted to the next generation through persistent alterations in maternal endocrine and metabolic regulation. In this study, using immunohistochemistry, quantitative RT-PCR, and Western blotting, we assessed morphological features and HIF1-dependent processes in the fetal and adult brains of progeny of female rats exposed to maternal hypoxia (PMH). We identified a delay in progenitor cell differentiation into neurons at embryonic day 14, a decreased number of neurons in the hippocampus, an increased number of astrocytes in the prefrontal cortex, and a decreased number of astrocytes in the raphe nuclei of the PMH rats. However, no significant changes were observed in HIF1α protein levels or in the protein levels of HIF1-dependent gene products in the examined brain structures. Thus, the transgenerational effect of maternal hypoxia is manifested as structural disturbances of brain development but is not accompanied by changes in HIF1-dependent metabolism. Full article