Search Results (3,159)

In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as “aerobic glycolysis”. Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, “The Astrocyte Neuron Lactate Shuttle Hypothesis” and “The Efficiency Tradeoff Hypothesis,” respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate. Full article

Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder with high morbidity and mortality, despite advances in aneurysm securing and neurocritical care. Clinical outcomes are determined by early brain injury (EBI), delayed cerebral ischemia (DCI), hydrocephalus, and long-term cognitive impairment, extending beyond the traditional focus on large-vessel vasospasm alone. Emerging evidence identifies the dysfunction of the glymphatic system and meningeal lymphatic pathway, the brain’s primary clearance pathways, as a central and unifying mechanism linking acute hemorrhagic injury to delayed and chronic neurological sequelae. Following SAH, acute intracranial pressure elevation, subarachnoid blood clot burden, loss of arterial pulsatility, venous congestion, astrocytic aquaporin-4 perivascular depolarization, and neuroinflammation converge to suppress cerebrospinal fluid–interstitial fluid exchange and outflow in glymphatic system and subsequent meningeal lymphatic drainage. Persistent clearance failure promotes the retention of blood breakdown products, inflammatory mediators, and metabolic waste, amplifying microvascular dysfunction, cortical spreading depolarizations, blood–brain barrier disruption, and secondary ischemic injury. Importantly, accumulating data highlight venous pathology and meningeal lymphatic impairment as critical, yet underappreciated, contributors to delayed injury and post-SAH hydrocephalus. In this review, we synthesize the current knowledge of the physiological organization of glymphatic and meningeal lymphatic systems, delineate the mechanistic and molecular drivers of their dysfunction after SAH, and discuss clinical implications for EBI, DCI, hydrocephalus, and long-term cognitive outcomes. We further outline future directions, including translational imaging, biomarker development, and therapeutic strategies targeting clearance pathways, to advance disease-modifying approaches in SAH. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article

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 (CREB). 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