Neuroglia

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article