CNS & neurological disorders drug targets最新文献

{"title":"Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.","authors":"Sheekha Chaudhary, Sanchit Dhankhar, Monika Saini, Thakur Gurjeet Singh, Samrat Chauhan, Viney Kumar","doi":"10.2174/0118715273491538261009064612","DOIUrl":"https://doi.org/10.2174/0118715273491538261009064612","url":null,"abstract":"<p><p>More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Hypothesis to Clinical Validation: A Bibliometric Mapping of Immunotherapy for Neurodegenerative Proteinopathies (2000-2025).","authors":"Ayşenur Budak Savaş, Fatma Yeşilyurt, Ahmet Hacimuftuoglu","doi":"10.2174/0118715273531307261012100737","DOIUrl":"https://doi.org/10.2174/0118715273531307261012100737","url":null,"abstract":"<p><strong>Introduction/objective: </strong>For twenty-five years, despite persistent challenges, the field of neurodegenerative disease has remained committed to a single hypothesis: targeting the immune system directly against misfolded proteins accumulating in the brain. Today, this approach has produced a clinical counterpart, with three monoclonal antibodies now approved, although the field is still progressing toward clinical validation. However, the research lines, countries, institutions, and journals through which this point was reached, and how far that validation has actually progressed, have remained largely unexamined.</p><p><strong>Methods: </strong>This study analyzes 9,863 articles published between 2000 and 2025 using bibliometric methods to map the field's intellectual structure, productivity patterns, and the thematic evolution shaped around four turning points.</p><p><strong>Results: </strong>The findings reveal a nonlinear trajectory. Annual output rose from a steady pace in the early 2000s to a sudden surge after 2019, exceeding 900 publications per year. Research output is heavily concentrated in the United States, while impact is concentrated among a small number of core journals and prolific authors. Only 47 journals account for one-third of the literature, and roughly four out of five authors have contributed only a single publication to the field. While the amyloid hypothesis continues to rest on strong genetic foundations, which protein species is actually neurotoxic, soluble oligomers or deposited plaques, remains an open question, and this keeps alive the debate over what clinical trials are truly measuring. The safety of approved drugs, particularly ARIA-related imaging abnormalities, and the challenge of delivering treatment across the blood-brain barrier stand out as fronts the field has yet to overcome.</p><p><strong>Discussion: </strong>Perhaps the most notable signal is that this accumulated progress now appears to be extending beyond Alzheimer's disease: thematic patterns suggest the same immunotherapeutic logic is beginning to extend toward Parkinson's disease and other proteinopathies.</p><p><strong>Conclusion: </strong>The study presents, within a single framework, the critical periods the field has passed through, who has led this journey, and which questions remain unanswered.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overview of the Mechanistic Potential of Serotonin Reuptake Transporters in Depression.","authors":"Sonia Singh, Kirti Baghel, Ashima Ahuja, Keshav Bansal","doi":"10.2174/0118715273467000261004044651","DOIUrl":"https://doi.org/10.2174/0118715273467000261004044651","url":null,"abstract":"<p><p>Depression is considered to be one of the most common psychiatric disorders that affect millions of people, despite a large amount of unrecorded data. This disorder has been associated with feelings of hopelessness, sleep disturbances, and even suicidal thoughts. However, the serotonin hypothesis emerged in the 1960s, suggesting that serotonin was one of the key neurotransmitters associated with depression by regulating mood, emotion, and cognitive effects. The serotonin reuptake transporter (SERT) plays a vital role in maintaining homeostasis by facilitating the reuptake of synaptic serotonin into presynaptic neurons. The dysregulation of SERT has been potentially involved in the pathophysiology of depressive disorder and its related disorders. This manuscript provides an overview of the pharmacological aspects of SERT, including its mechanism of action, regulation, role in depression, and potential therapeutic targets. Current antidepressant research is increasingly focused on the development of highly selective and rapid-acting modulators of the SERT to overcome the delayed onset of action and limited efficacy associated with conventional selective serotonin reuptake inhibitors (SSRIs). Emerging strategies include designing allosteric SERT inhibitors that bind to alternative sites on the transporter, potentially enhancing selectivity while minimizing adverse effects. In parallel, the integration of pharmacogenomic insights into clinical practice seeks to personalize antidepressant therapy based on individual genetic variations-particularly polymorphisms in the SLC6A4 gene and related molecular markers-thereby improving therapeutic precision and overall treatment outcomes. Allosteric modulation of selective serotonin reuptake inhibitors and pharmacogenomics- guided treatment selection highlight the need to maximize therapeutic outcomes and fulfill the unmet needs of patients who suffer from depression.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Shared Molecular Mechanisms in Alzheimer's, Parkinson's, and Neuropathic Pain: Targeting p38 MAPK and Wnt/β-Catenin Pathways.","authors":"Anjali Bhardwaj, Neha Parveen, Rajesh Singh, Bharat Bhushan","doi":"10.2174/0118715273492918261001111401","DOIUrl":"https://doi.org/10.2174/0118715273492918261001111401","url":null,"abstract":"<p><p>Neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), and Neuropathic Pain (NP), share overlapping molecular and cellular mechanisms that contribute to progressive neuronal dysfunction, neuroinflammation, and impaired neural repair. Although these conditions present with distinct clinical manifestations, accumulating evidence indicates that dysregulation of the p38 mitogen-activated protein kinase (p38 MAPK) and Wnt/β-catenin signaling pathways represents a common pathogenic axis underlying disease initiation and progression. Activation of p38 MAPK amplifies inflammatory signaling, mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and glial activation, whereas suppression of Wnt/β-catenin signaling disrupts synaptic plasticity, blood-brain barrier integrity, neurogenesis, and neuronal survival. The reciprocal interaction between these pathways further exacerbates amyloid-β accumulation, dopaminergic neuronal degeneration, tau hyperphosphorylation, central sensitization, and persistent neuroimmune activation, thereby linking cognitive decline, motor impairment, and chronic pain. This review comprehensively examines the molecular crosstalk between p38 MAPK and Wnt/β-catenin signaling across AD, PD, and NP, highlighting their roles in regulating neuroinflammation, oxidative stress, mitochondrial homeostasis, and neuronal resilience. In addition, it summarizes emerging pharmacological agents, natural bioactive compounds, and targeted therapeutic strategies designed to inhibit p38 MAPK activation or restore Wnt/β-catenin signaling to promote neuroprotection and functional recovery. Particular emphasis is placed on the translational potential of dual-pathway modulation as a disease-modifying approach that addresses shared pathological mechanisms rather than isolated disease- specific manifestations. By integrating current experimental and clinical evidence, this review provides a unified mechanistic perspective, identifies promising therapeutic opportunities for developing more effective interventions against neurodegenerative disorders and neuropathic pain, and outlines the remaining challenges for future translational research.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging-driven Mechanisms Underlying Parkinson's Disease Pathogenesis: Molecular, Cellular, and Systemic Perspectives.","authors":"Amanda Yee Jing Lee, Leanne Khoo, Khuen Yen Ng, Cien Leong Chye, Jia Yee Lee, Yi Ko, Soi Moi Chye","doi":"10.2174/0118715273467333261002070852","DOIUrl":"https://doi.org/10.2174/0118715273467333261002070852","url":null,"abstract":"<p><p>Aging is a major risk factor for Parkinson's Disease (PD) and is linked to various biological processes at the molecular, cellular, and systemic levels. At the molecular level, aging-related oxidative stress, mitochondrial dysfunction, genetic factors, and impaired proteostasis contribute to dopaminergic neuronal death. Cellular alterations include persistent glial cell activation, autophagylysosomal dysfunction, and impaired cellular repair mechanisms. At the systemic level, aging is associated with metabolic imbalance, gut microbiota dysbiosis, and immune system dysfunction, which may contribute to PD pathogenesis through the gut-brain axis. Antioxidant therapy, stem cell therapy, anti-aging agents, and modulation of gut-brain communication have shown promise in the management of PD. Lifestyle modifications, including dietary changes and regular exercise, may exert anti-aging effects that could help delay or prevent the onset of PD. Emerging anti-aging interventions, including N-acetylcysteine and plant-derived compounds that support mitochondrial function, have also demonstrated therapeutic potential for PD.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prolactin and Neuroendocrine Regulation in Brain Injury: Mechanisms of Adaptive Plasticity and Therapy Strategies.","authors":"Prashant Tiwari, Phool Chandra, Sunil Kumar Kadiri","doi":"10.2174/0118715273472775260929093840","DOIUrl":"https://doi.org/10.2174/0118715273472775260929093840","url":null,"abstract":"<p><strong>Background: </strong>Acquired Brain Injuries (ABIs) represent a significant worldwide health challenge, with few specific medicines available to enhance recovery. Growing data underscores neuroendocrine dysfunction, especially with prolactin as a relatively overlooked yet potentially alterable element in neuronal regeneration. Hormonal signals regulate synaptic remodeling, neurogenesis, and glial regulation, rendering this a significant and current field of study.</p><p><strong>Methodology: </strong>This review integrates evidence from clinical trials, animal models, and molecular research to assess prolactin's role in post-injury neural adaptation, with an emphasis on astrocyte activation, microglial responses, neuronal survival, and endocrine-neural connections.</p><p><strong>Results: </strong>Prolactin has a dual function, as suggested by the evidence: a brief elevation may promote neuroprotection, synaptic recovery, and blood-brain barrier integrity, whereas sustained hyperprolactinemia correlates with cognitive deterioration, neuropsychiatric symptoms, and dopaminergic dysfunction. Prolactin receptor signaling appears to be a common feature of neuroinflammatory and glial events.</p><p><strong>Discussion: </strong>These results illustrate the context-specific action of prolactin and demonstrate the importance of distinguishing between adaptive and maladaptive signaling. The addition of endocrine profiling to neurorehabilitation could open new avenues for individualized treatment.</p><p><strong>Conclusion: </strong>This review presents prolactin as a potential, though not yet fully confirmed, modulator of ABI recovery. Further clinical research is required to enable the translation of these insights into maximal diagnostic and therapeutic benefit.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Progressive Multiple Sclerosis and the Therapeutic Potential of BTK Inhibitors Based on EBV-driven B Cell-microglia Interactions.","authors":"Leiyun Huang, Jinghan Hu, Song Pang, Yu Zhang, Yifan Wang, Yongzhen Liu, Shangwei Wu, Qingjin Cai, Tianqing Xiong, Jing Qian","doi":"10.2174/0118715273503588260911101820","DOIUrl":"https://doi.org/10.2174/0118715273503588260911101820","url":null,"abstract":"<p><p>Progressive Multiple Sclerosis (PMS) remains a major cause of irreversible disability in Multiple Sclerosis (MS), yet current disease-modifying therapies incompletely address the compartmentalized Central Nervous System (CNS) inflammation, sustained microglial activation, chronic demyelination, and axonal degeneration that characterize progression. This topic is timely because the evidence linking Epstein-Barr Virus (EBV) to MS susceptibility, the recognition of B cell-myeloid interactions within the CNS, and the clinical development of CNS-penetrant Bruton's Tyrosine Kinase inhibitors (BTKi) now converge on a common translational question: whether a connected EBV- B cell-microglia-BTK axis can explain part of progression independent of relapse activity and inform therapy for PMS. EBV establishes lifelong latency in memory B cells and may contribute to MS through molecular mimicry, aberrant antigen presentation, and persistent pro-inflammatory signaling. In progressive disease, B cells can interact with microglia and macrophages to sustain compartmentalized inflammation, while BTK links B-cell receptor and myeloid Fc receptor signaling. This review synthesizes EBV-associated B-cell dysregulation, B cell-microglia crosstalk, BTK biology, BTKi trial evidence, biomarkers, and safety considerations in an evidence-stratified framework. Rather than presenting a linear causal model, we distinguish established observations from emerging mechanisms and speculative hypotheses. We propose that this integrated pathophysiological framework may help clarify patient stratification, CNS target engagement, and rational therapeutic development for PMS while defining the limits that future studies must address.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Footprints of Diabetic Peripheral Neuropathy: Investigating Transcriptional Modulation of Sphingolipid Metabolism, Myelin-specific Genes and Neurotrophic Factors Under Elevated Glucose and Harnessing Therapeutic Potential of DHA and ALA.","authors":"Suman Samaddar, Moqbel Ali Moqbel Redhwan, Mohan Muttanahally Eraiah","doi":"10.2174/0118715273459828260925063553","DOIUrl":"https://doi.org/10.2174/0118715273459828260925063553","url":null,"abstract":"<p><strong>Background: </strong>Research has shown that disturbances in sphingolipid metabolic homeostasis are significant contributors to Diabetic Peripheral Neuropathy (DPN). Ceramides and their metabolites are cell signaling molecules involved in islet cell function, insulin resistance, β-cell apoptosis, and neurodegeneration. However, diabetes-related abnormalities in sphingolipid metabolism in peripheral nerves have received little attention in the scientific literature.</p><p><strong>Methods: </strong>Neuroblastoma cells (Neuro2a) were exposed to high glucose (50 mM). Alpha-lipoic acid (ALA; 50 μM) and docosahexaenoic acid (DHA; 50 μM) were considered therapeutic interventions. Myelin-specific and neurotrophin gene expression was also studied in Schwann cells (IMS32) and in DPN induced in mice with streptozotocin (150 mg/kg).</p><p><strong>Results: </strong>High glucose reduced cell viability, compromised membrane integrity, and induced apoptosis, as revealed by MTT, propidium iodide, and Annexin V/PI assays. RT-qPCR analysis showed significantly higher mRNA levels of genes that regulate the de novo, salvage, and sphingomyelinase pathways. Bioactive sphingolipids (ceramide, sphingosine, ceramide-1-P, and sphingosine-1-P) were found elevated by ELISA. The apoptotic (AIF, Bak, Bax, Cas-3, Cas-9, and p53) and inflammatory (IL-6, IL-1β, TNF-α, iNOS, and NF-κB) genes were upregulated, while Bcl-2 was downregulated. mRNA expression of myelin-specific proteins and neurotrophic factors was also reduced in the sciatic nerves of DPN mice and HG-treated IMS32 cells. DHA and ALA were found to normalize nearly all anomalies induced by hyperglycemia.</p><p><strong>Discussion: </strong>The genes regulating the de novo, salvage, and sphingomyelinase pathways were differentially modulated in diabetic conditions. We suggest that targeting those genes would be a safer approach to ameliorate ceramide-mediated nerve damage in diabetes. Myelin-specific genes, including NT-3, NT-4, NGF-β, BDNF, CNTF, and GDNF, were downregulated in the sciatic nerve of neuropathic animals. Treatment with ALA and DHA proved beneficial in reversing the conditions; hence, supplementation with ALA and DHA, in addition to the standard anti-diabetic treatment regimen, is suggested.</p><p><strong>Conclusion: </strong>These findings suggest significant implications of hyperglycemia on sphingolipid metabolic impairment, which, in turn, impacts cell integrity and viability, myelin stability, and neurodegeneration.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation and Autophagy in Neurodegeneration: Cellular Mechanisms and Therapeutic Strategies.","authors":"Anushka Verma, Swatantra Kumar Singh Kushwaha, Neelottama Kushwaha, Sayantan Dutta, Parul Nigam","doi":"10.2174/0118715273459017260922073618","DOIUrl":"https://doi.org/10.2174/0118715273459017260922073618","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal dysfunction and loss, often accompanied by toxic protein aggregation and chronic neuroinflammation. Increasing evidence indicates that dysregulated autophagy and persistent inflammatory responses are central drivers of disease onset and progression. Autophagy, a fundamental cellular degradation and recycling process, is essential for maintaining neuronal homeostasis by removing damaged organelles and misfolded proteins through mechanisms such as macroautophagy and mitophagy. However, key regulators of this pathway, including ULK1, Beclin-1, LC3, and p62/SQSTM1, are frequently impaired in neurodegenerative conditions, leading to the accumulation of pathogenic proteins such as tau, α-synuclein, and amyloid-β. Concurrently, aberrant activation of microglia and inflammasomes promotes the sustained release of pro-inflammatory cytokines, creating a neurotoxic environment that exacerbates neuronal injury. This review examines the molecular crosstalk between autophagy and neuroinflammation, with particular emphasis on disease-specific mechanisms, including LC3-associated endocytosis (LANDO) in Alzheimer's disease, tau-mediated pathology, and dopaminergic neurodegeneration in Parkinson's disease. Importantly, this review introduces a unifying conceptual framework in which neuroinflammation and autophagy are integrated as a dynamic, stagedependent immune-autophagy axis that governs neurodegenerative disease progression and therapeutic responsiveness. In addition, emerging multimodal therapeutic strategies targeting both autophagic flux and immune modulation are discussed, including mTOR inhibitors, mitophagy enhancers, GLP-1 receptor agonists, and nanomedicine-based delivery systems. Advances in three-dimensional organoids, induced Pluripotent Stem Cell (iPSC) models, and biomarker-driven clinical trials are further enhancing translational potential. In conclusion, understanding the interplay between autophagy and neuroinflammation provides critical insights into the pathophysiology of neurodegeneration and offers promising avenues for the development of targeted, disease-modifying therapies.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol's Therapeutic Role in Sepsis-Associated Encephalopathy.","authors":"Shuoyan Dong, Qian Cui, Lei Zong, Yixin Xue, Lina Zhao, Yun Li","doi":"10.2174/0118715273502075260910113533","DOIUrl":"https://doi.org/10.2174/0118715273502075260910113533","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Sepsis-Associated Encephalopathy (SAE) represents a lifethreatening complication of sepsis, whose pathogenesis is driven by intestinal dysbiosis through bidirectional gut-brain axis signaling. Resveratrol, a neuroprotective natural polyphenol, exerts anti-SAE effects in a microbiota-dependent manner; nevertheless, existing mechanistic evidence has not been systematically integrated. This review comprehensively summarizes its multitiered protective signaling cascades centered on gut-brain crosstalk.</p><p><strong>Methods: </strong>We systematically retrieved relevant literature published between January 2006 and July 2026 from mainstream databases in accordance with the PRISMA-S reporting standard. We integrated CLP/LPS septic animal and cellular data, and compared auxiliary evidence from non-septic models without direct extrapolation.</p><p><strong>Results: </strong>Preclinical septic animal studies confirmed four core protective axes of resveratrol centered on gut microbiota remodeling: (1) reshaping intestinal flora to limit LPS translocation; (2) stabilizing intestinal and cerebral tight junctions via SIRT1/NF-κB signaling; (3) elevating gut-derived shortchain fatty acids to inhibit glial pro-inflammatory activation; (4) activating Nrf2/HO-1 to relieve cerebral mitochondrial oxidative injury. Reciprocal fecal microbiota transplantation, germ-free and antibiotic depletion assays verified gut flora as an indispensable intermediate mediator linking oral resveratrol to neurological recovery. Non-septic model data provided auxiliary molecular references but cannot be extrapolated to SAE without septic-specific validation. Major translational obstacles include low oral bioavailability, narrow therapeutic window, and conflicting efficacy under combined ICU routine medications.</p><p><strong>Discussion: </strong>All cerebral pathological lesions (neuroinflammation, glial polarization, oxidative stress, BBB damage) originate from gut dysbiosis and endotoxin translocation in SAE, which establishes the gut-brain axis as the core therapeutic target of resveratrol. Repeated redundant mechanistic descriptions across pathways were condensed and overlapping glial sections merged in this revised minireview to meet journal word limits. Indirect non-septic evidence lacks the systemic endotoxin storm characteristic of SAE, thus only serves as supplementary reference. Novel microbiota-targeted delivery formulations are promising solutions to overcome resveratrol's pharmacokinetic defects.</p><p><strong>Conclusion: </strong>Resveratrol alleviates SAE through multi-modal gut-brain axis regulation. Novel microbiota- targeted delivery carriers and standardized clinical trials focusing on delayed intervention are urgently needed to overcome translational limitations and facilitate the clinical application of resveratrol as an adjuvant therapy for SAE.</p>","PeriodicalId":93947,"journal":{"name":"CNS & neurological disorders drug targets","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149042832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}