Search Results (5,521)

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Neurodegenerative diseases (NDs) are increasingly considered neurometabolic disorders driven by early mitochondrial dysfunction, neuroinflammation, and synaptic alterations that precede clinical symptoms. This review summarises pre-clinical and experimental evidence suggesting that intermittent fasting (IF) may influence these early pathogenic processes by promoting metabolic switching, enhancing autophagy and mitochondrial quality control, and modulating neuroimmune pathways. We discuss recent advances in biomarker research supporting the early detection of neurodegenerative changes, including ultrasensitive analytical platforms that can identify neuronal, glial, and synaptic injury during preclinical stages. By integrating these biomarker developments with findings from human and experimental intermittent fasting studies, we highlight how high-sensitivity assays provide quantifiable insights into the neurometabolic effects of fasting. Furthermore, we discuss how precision nutrition strategies incorporating multimarker panels, phenotypic and epigenetic signatures, and longitudinal multi-omics profiling may facilitate personalised intermittent fasting protocols and improve monitoring of biological responses. Overall, these findings underscore the relevance of a clinical biochemistry perspective integrating advanced biomarker technologies to evaluate the neurometabolic effects of intermittent fasting as a potential early neuroprotective strategy for individuals at risk of neurodegeneration. Full article

Glaucoma, characterized by progressive retinal ganglion cell degeneration and optic nerve damage, is the leading cause of irreversible blindness worldwide. Multiple risk factors influence the pathogenesis and progression of glaucoma. Food-derived bioactive components have emerged as a new area of interest to overcome the limitations of current standard treatments due to their antioxidant and anti-inflammatory activities and multi-target mechanisms. In this context, various plant-derived foods, such as Lycium barbarum, Ganoderma lucidum, Cryptotanshinone, Scutellaria baicalensis, Silybum marianum, Astragalus membranaceus, Ginkgo biloba, Panax ginseng, Crocus sativus, and resveratrol, have shown potential mechanisms for treating glaucoma. These bioactive components may address oxidative damage, neuroinflammation, and elevated intraocular pressure, which may be due to the modulation of multiple signaling pathways, including JAK2/STAT3, PI3K/AKT, MEK/ERK/CREB, cAMP/PKA/CREB, and others. However, further clinical trials are needed to validate dosage, bioavailability, and long-term safety. This review highlights the potential of bioactive components from plant-derived foods, offering a reference for further investigation into their effects on glaucoma. Full article

Background: Obesity is a chronic metabolic disease that has emerged as a major global public health concern. Obesity complications refer to a range of metabolic, neurological and behavioral disorders. Complex interaction mechanisms exist between obesity and the brain, including neuroendocrine regulation, center inflammatory responses, the gut–brain axis, and obesity-related cognitive impairment. Polyphenols are naturally occurring bioactive compounds widely found in plants. Recent research indicates that polyphenols may modulate the brain through multiple pathways, thereby ameliorating obesity complications. However, no data set available to summarize neuroregulatory effects of dietary polyphenols on obesity complication. Methods: The latest data available were collected to review research progress focusing on neuroregulatory roles of polyphenols on obesity complication. Results: This review summarizes the interaction between obesity and the brain and further explores the effects of polyphenols on obesity-related neurological disorders, with particular emphasis on their roles in appetite regulation, central neuroinflammation, brain leptin and insulin resistance, gut–brain axis modulation, and cognitive improvement. Finally, future perspectives are discussed. Conclusions: This paper may provide a new theoretical support and research direction for the potential of polyphenols against obesity-related neurological complications. Full article

The relationship between epilepsy, obesity, and metabolic syndrome (MetS) has emerged as a rapidly evolving area of neurobiology inquiry. Emerging evidence suggests that epilepsy extends beyond neuronal hyperexcitability, reframing it as a systemic condition characterized by significant metabolic dysregulation. Converging supports a bidirectional relationship while seizures, antiseizure medications (ASM), and neuroinflammation induce exacerbate potentiate epileptogenesis through shared molecular pathways. At the cellular level, chronic epileptic activity induces oxidative stress, mitochondrial dysfunction, and the activation of microglia and astrocytes. This, in turn, leads to the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. These mediators traverse the blood-brain barrier (BBB), subsequently modifying insulin signaling, and disrupting glucose homeostasis, which collectively fosters a pro-inflammatory and insulin-resistant environment. Furthermore, antiseizure medications such as valproate can exacerbate these effects by directly impairing insulin receptor signaling and altering adipokine production, ultimately contributing to weight gain and systemic metabolic dysregulation. Obesity and MetS induce neuroinflammatory and excitotoxic states that promote seizure onset via leptin resistance, reduced adiponectin levels, and compromised AMP-activated protein kinase (AMPK) signaling. Emerging evidence emphasizes the gut-brain axis as a crucial regulator in this reciprocal interaction. Dysbiosis, altered microbial metabolites (e.g., short-chain fatty acids), and heightened intestinal permeability facilitate systemic inflammation and BBB disruption, enhancing neuronal excitability. Insulin resistance in the brain disrupts synaptic transmission, impairs mitochondrial biogenesis, and compromises redox equilibrium, perpetuating a pathological cycle linking metabolic stress to epileptic activity. This review synthesizes the cellular, molecular, and systemic pathways connecting epilepsy, obesity, and MetS, and proposes that epilepsy be reconceptualized as a neuro-metabolic disorder. Insights into these convergent pathways provide a rationale for novel therapeutic strategies that simultaneously target seizure control and metabolic regulation, encompassing microbiota modulation, antioxidant therapy, and insulin-sensitizing interventions with the overarching aim of restoring neuro-metabolic homeostasis. Full article

Neurodegenerative diseases of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, represent a growing health challenge in ageing populations. Among the mechanisms underlying these disorders, increasing attention has been directed toward the role of cellular senescence. This process, triggered by chronic cellular and oxidative stress as well as DNA damage, leads to irreversible cell-cycle arrest and the development of the senescence-associated secretory phenotype (SASP). Within the central nervous system, the accumulation of senescent cells induces chronic inflammation, blood–brain barrier disruption, and progression of neurodegenerative processes. In this review, we present current evidence regarding the mechanisms of cellular senescence in the central nervous system, with particular emphasis on the role of SASP in neuroinflammation, vascular dysfunction, and neural tissue damage. Experimental and clinical data supporting the involvement of cellular senescence in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis are discussed. The review also covers methods for identifying senescent cells in the brain, including molecular marker-based approaches and machine learning-based tools. Importantly, we discuss the methodological limitations of commonly used senescence markers, such as their limited specificity and the risk of false-positive detection, particularly in the heterogeneous cellular environment of the central nervous system. Strategies to improve detection reliability discussed in this review include the use of multimarker signatures, analysis of SASP components using qRT-PCR and ELISA, as well as transcriptomic approaches such as RNA sequencing and single-cell RNA sequencing. Furthermore, we analyze therapeutic strategies targeting senescent cells—senolytics, senomorphics, and SASP modulation—together with their limitations and associated clinical challenges. The collected evidence indicates that precise characterization of senescent cell populations in the brain is essential for the development of disease-modifying therapies for neurodegenerative disorders. Full article

Background: Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited. Objectives: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on α-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations. Methods: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance. Results: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders. Conclusions: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability. Full article

Genotoxic stress, which includes DNA damage and the mis-localization of DNA and RNA, is a defining feature of tauopathies, Alzheimer’s disease, and several other neurodegenerative disorders. Recent findings indicate that activation of the innate immune system in response to genotoxic stress can drive harmful neuroinflammation, compromise neuronal integrity, and promote neurodegeneration. Multiple innate immune sensors of genotoxic stress have recently been discovered, but the contributions of many of these emerging nucleic acid–sensing pathways in neurodegenerative disease pathogenesis remain largely unexplored. Z-DNA binding protein 1 (ZBP1) is one such recently discovered genotoxic stress sensor that has been shown to incite various forms of cell death as well as proinflammatory cytokine production in response to left-handed Z conformations of DNA (Z-DNA) and RNA (Z-RNA). Here, we show that ZBP1 deletion provides protection against tau pathology and neuronal loss in the PS19 mouse model of tauopathy. Moreover, we find that this rescue of tauopathy seen with ZBP1 ablation is associated with dampened activation of microglia and astrocytes. These findings identify ZBP1 as a pivotal genotoxic stress sensor that drives tau pathology, gliosis, and neuronal loss in tauopathy. This work further suggests that targeting ZBP1 may offer a therapeutic strategy to treat tau-mediated neurodegenerative disease. Full article

The prevalence of Parkinson’s disease (PD) is projected to rise, stressing the urgency for disease-modifying therapies. Its complex pathophysiology, characterized by α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation, continues to complicate therapeutic development. Mounting evidence implicates neuroinflammation as both a driver and consequence of disease progression. This highlights the need to address both neuronal loss and the established dysfunctional microenvironment. Consequently, stem cell-based treatments have generated interest for their immunomodulatory, neuroprotective, and regenerative potential. However, therapeutic outcomes are strongly influenced by stem cell type and route of administration, which together determine whether effects are predominantly regenerative or restorative. In this review, we introduce a conceptual framework that situates stem cell therapies for PD along a regenerative–restorative continuum. Regenerative therapies include fetal ventral mesencephalic, embryonic, and induced pluripotent stem cells. When delivered intracerebrally, they aim to reconstruct dopaminergic circuitry through differentiation and engraftment. In contrast, restorative approaches include mesenchymal stem cells, which exert paracrine and immunomodulatory effects to promote neuroprotection and functional stabilization of the neuronal environment. Multilineage-differentiating stress-enduring cells and neural stem cells exhibit both regenerative and restorative features, to differing extents. This framework integrates mechanistic and clinical evidence that may help clarify distinctions across stem cell approaches and inform future translational development in PD. Full article

Systemic inflammation leading to neuroinflammation is a matter of concern in recent years because of its implication with neurological disorders. Selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists have shown promising anti-inflammatory effects in various neurodegenerative diseases. With pioglitazone being one such PPAR-γ agonist, our study was aimed at investigating the role of pioglitazone on oxidative stress and cognitive changes against LPS-induced neuroinflammation in rats. In-house-bred male Wistar rats, about six weeks old, were utilized for the present study. They were categorized as A (preventive) and B (curative) groups, each with five subgroups: control (1A and 1B), neuro-inflammatory (2A and 2B), and three different dosages of pioglitazone treatment (3A, 3B, 4A, 4B, and 5A, 5B). After the experimental period, cognitive changes were examined by behavioral tests. Brain homogenate was used for biochemical parameters. Deteriorated memory, superoxide dismutase activity and increase in lipid peroxidation in the brain tissue induced by LPS exposure were substantially alleviated (p < 0.001) by pioglitazone treatment. These results suggest that pioglitazone may be neuroprotective against LPS-induced neuroinflammation. Full article

Background: Herpes simplex virus (HSV), Epstein–Barr virus (EBV), and cytomegalovirus (CMV) establish lifelong latency in sensory neurons, lymphoid tissue, and myeloid–endothelial cells, respectively. A substantial proportion of adults worldwide are infected with all three viruses and may experience concurrent herpesvirus latency, yet they have largely been studied independently. This review examined whether latent and intermittently reactivating herpesviruses share overlapping inflammatory signatures and whether their combined presence contributes to chronic inflammatory burden. Methods: A narrative integrative review was conducted using MEDLINE, Embase, and Google Scholar (inception–October 2025). Evidence from thirty-one cohort studies and mechanistic investigations spanning virology, immunology, neurology, and clinical medicine was synthesized. Results: Herpesvirus reactivation rates ranged from 23% in general Intensive Care Unit (ICU) populations to 85% in severe COVID-19. Concurrent reactivation of multiple viruses occurred in 34–63% of critically ill patients and was associated with worse clinical outcomes. Notably, simultaneous CMV and EBV reactivation independently predicted mortality (adjusted hazard ratio, 3.17; 95% CI, 1.41–7.13). Across infections, overlapping inflammatory biomarkers, including IL-6, TNF-α, CRP, and PGE₂, were consistently elevated, reflecting convergent activation of IFN and NF-κB signaling pathways. Mechanistic studies suggest cross-compartment immune priming, where CMV-driven T-cell exhaustion facilitates EBV reactivation, and viral cytokine signaling enhances HSV-associated neuroinflammation. Conclusions: HSV, EBV, and CMV triple latency may represent an underrecognized contributor to chronic inflammation in immunocompetent hosts. Understanding this multi-virus inflammatory network may inform mechanistic research, biomarker-guided risk stratification, and therapeutic strategies targeting convergent inflammatory pathways. Prospective interventional studies incorporating concurrent multi-virus monitoring are needed to clarify causal relationships. Full article

Stroke remains a major cause of morbidity and mortality worldwide. Although reperfusion therapies and secondary prevention have advanced, the global stroke burden continues to rise, driven by increasing rates of hypertension and diabetes mellitus. Type 2 diabetes (T2DM) increases the risk of acute ischemic stroke (AIS) through mechanisms involving chronic hyperglycemia, endothelial dysfunction, inflammation, and accelerated atherogenesis. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents for cardiovascular and cerebrovascular risk reduction in patients with T2DM. Beyond their glucose-lowering properties, GLP-1RAs improve blood pressure regulation and lipid metabolism, as mentioned in the 2025 AHA Journal guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults. Emerging preclinical and clinical evidence indicates that GLP-1RAs also provide direct neurovascular protection by stabilizing the blood–brain barrier, modulating neuroinflammation, and promoting neuronal survival. These mechanisms may reduce ischemic injury, improve recovery after stroke, and protect against cognitive decline. Major cardiovascular outcome trials have demonstrated significant reductions in major adverse cardiovascular events and, to a lesser degree, non-fatal stroke among patients receiving GLP-1RAs. This narrative review evaluates current evidence on the neurovascular, cardiometabolic, and anti-inflammatory actions of GLP-1RAs and their potential role in mitigating stroke risk and promoting cerebrovascular health. Additionally, it highlights gaps in the literature, explores clinical and guideline implications, and outlines future directions for integrating GLP-1RA therapy into comprehensive stroke prevention and recovery strategies. Full article

Diabetic retinopathy (DR) is more than a capillary disorder. Diabetes affects neurons, glial cells, vascular cells, and immune signals within the retinal neurovascular unit (NVU). Retinal neurovascular coupling (NVC) is a useful functional marker of NVU integrity because it reflects the rise in local blood flow that follows neural activity. Many human flicker-light studies report smaller vessel dilation or weaker flow responses in diabetes. This finding can appear even in patients without clear fundus lesions. When NVC is reduced, retinal tissue may receive less oxygen. Lower oxygen delivery can raise oxidative stress and promote inflammation. These changes can then worsen vascular injury. This review describes key NVC pathways and diabetes-related NVU changes in Müller glia, astrocytes, microglia, pericytes, and endothelial cells. The review highlights sympathetic activation as a common stress signal. Pain, anxiety, perioperative stress, and sleep loss can increase sympathetic activity and circulating catecholamines. In the diabetic retina, vascular reserve is often limited. Under these conditions, catecholamines can increase mural cell constriction, reduce nitric oxide (NO)-dependent relaxation, and increase endothelial activation and barrier strain. These effects can shift the baseline state of glial and immune cells and further weaken NVC. The review also summarizes translational tools that can test these links. These tools include heart rate variability, standardized NVC protocols with diameter and flow measures, and retinal organoid and organ-on-a-chip platforms with controlled adrenergic exposure. The review discusses perioperative care packages that reduce stress responses, protect sleep, and manage glucose as practical ways to support retinal microcirculation. More longitudinal human studies are still needed. Retina-specific perioperative endpoints are also needed to clarify causality and to guide intervention trials. Full article

Type 2 Diabetes (T2D) is characterized by the toxic aggregation of human islet amyloid polypeptide (hIAPP or amylin) within pancreatic β-cells. IAPP is also a neuropancreatic hormone that plays a significant role in Alzheimer’s disease (AD) by co-depositing with amyloid-beta (Aβ) and Tau, supporting the Type 3 Diabetes (T3D) hypothesis. Soluble IAPP accelerates Aβ aggregation through cross-seeding and causes neurotoxicity by impairing the blood–brain barrier and activating neuroinflammation. Melatonin inhibits these processes by disrupting hydrophobic interactions in both hIAPP and Aβ, preventing the formation of toxic β-sheet structures. Furthermore, melatonin promotes amyloid clearance via the glymphatic and lymphatic systems, protects neurons from oxidative damage, and reduces Tau hyperphosphorylation. This suggests that melatonin serves as a promising multitarget therapeutic agent for both metabolic and neurodegenerative disorders by modulating structural protein transformations. Full article

Multiple sclerosis is a chronic immune-mediated central nervous system disorder marked by neuroinflammation, demyelination, and neurodegeneration, and effectively modeled by experimental autoimmune encephalomyelitis. The objective of this study was to elucidate the roles of T follicular helper and T follicular regulatory cells in the progression of experimental autoimmune encephalomyelitis and to assess their association with IL-21 expression and central nervous system tissue pathology. In this study, experimental autoimmune encephalomyelitis was induced in 25 adult female C57BL/6 mice. Fluorescent double immunostaining for CXCR5 in combination with PD-1, ICOS, CD4, and FOXP3 was performed, along with the analysis of IL-21 mRNA expression. Histopathological assessment was conducted on the cerebrum, cerebellum, and medulla spinalis to evaluate neuroinflammation and myelin loss. A significant increase in CXCR5⁺PD-1⁺ and CXCR5⁺ICOS⁺ T follicular helper-like cells was observed in brain tissue, indicating immune activation and T follicular helper cell involvement. Simultaneously, a marked decrease in FOXP3⁺ T follicular regulatory-like cells suggested impaired immune tolerance and enhanced autoimmune activity. The infiltration of T follicular helper-like cells was identified as a key driver of inflammation and demyelination in the central nervous system. Additionally, the elevated IL-21 mRNA expression highlighted B cell activation and the initiation of antibody-mediated responses. These findings suggest that dysregulation of the T follicular helper/T follicular regulatory axis and elevated IL-21 expression contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis, providing further insight into the mechanisms underlying multiple sclerosis development. Full article