Molecular Neurobiology最新文献

{"title":"Advances in Extracellular Vesicle-Based Innovative Drugs Targeting Alzheimer's Disease.","authors":"Shangfeng Liu, Jueqin Lu, Jiaxin Liu, Huaxiang Liu, Zhongliang Liu, Danjing Yang, Xingqun Liang, Jun Xu","doi":"10.1007/s12035-026-06223-x","DOIUrl":"10.1007/s12035-026-06223-x","url":null,"abstract":"<p><p>The scarcity of effective therapies for Alzheimer's disease (AD) underscores the urgent need for innovative strategies. This review focuses on the targeted delivery of engineered small extracellular vesicles (sEVs, 30-150 nm). By capitalizing on their intrinsic properties as natural nanocarriers-including low immunogenicity and excellent biocompatibility-these EVs can be engineered to co-deliver therapeutic cargoes such as specific miRNAs, neurotrophic factors (e.g., BDNF), and nucleic acid modalities (e.g., siRNA/ASO targeting BACE1). While a single construct simultaneously delivering all these agents with proven in vivo synergy remains a conceptual framework rather than a validated reality, independent studies have demonstrated that EV-mediated delivery of each cargo type exerts beneficial effects on AD pathology, including Aβ clearance, Tau pathology alleviation, and neuroinflammation suppression. The intranasal administration offers a significant brain-targeting advantage by enabling direct nose-to-brain delivery, bypassing the blood-brain barrier and minimizing peripheral biodistribution. Recently, a phase I/II trial (Ruijin Hospital) demonstrated that intranasal MSC-EVs are safe and produce durable cognitive improvements (ADAS-Cog ↓ 2.33 points at week 12, sustained to - 3.98 points at week 36) in the medium-dose cohort, exceeding the minimal clinically important difference (MCID) of ≥ 2 points for AD. Based on these demonstrated clinical and preclinical evidence, we propose that rationally engineered EVs, following rigorous systematic pharmacology and safety assessments, hold transformative potential to pioneer a safe, efficacious, and non-invasive breakthrough therapy for AD, while acknowledging that critical challenges in GMP manufacturing, biodistribution, and regulatory approval remain to be resolved.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological Priming and Developmental Heterochrony as Organizing Concepts in Human iPSC Models of Autism Spectrum Disorder.","authors":"Pardis Jahandideh, Amirreza Bitaraf","doi":"10.1007/s12035-026-06252-6","DOIUrl":"10.1007/s12035-026-06252-6","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition in which diverse genetic risk factors converge on molecular pathways governing early brain development. Human-induced pluripotent stem cell (iPSC) and brain organoid models now permit direct interrogation of these pathways in patient-derived neural tissue and, in a subset of studies, reveal alterations in neural progenitor proliferation, cortical neurogenesis, synaptic maturation, and network excitability. A landmark iPSC study in macrocephalic idiopathic ASD introduced the concept of pathological priming of neural progenitors, durable reconfiguration of chromatin and transcriptional states that biases downstream developmental programs, and associated developmental heterochrony in neuronal gene networks, thereby linking early progenitor biology to selectively shifted trajectories of neuronal maturation and to macrostructural and functional abnormalities. This conceptual review synthesizes evidence for pathological priming and developmental heterochrony from human iPSC-derived neurons and brain organoids, focusing on the ASD subgroups in which timing mechanisms are best supported: macrocephalic idiopathic ASD, 16p11.2 and related copy number variants, and large-effect developmental regulators such as SYNGAP1. We summarize recurrent and inconsistent cellular and circuit phenotypes, evaluate multi-omic data implicating progenitor regulatory states in shaping developmental timing, and situate timing-focused mechanisms alongside synaptopathy, excitatory-inhibitory imbalance, critical-period, and neuroimmune models. We propose that disturbances in neurodevelopmental timing characterize specific ASD subgroups, particularly those with early brain overgrowth or large-effect developmental regulators, rather than ASD as a whole, and offer a useful organizing principle for integrating divergent findings and generating testable, timing-informed hypotheses for future experimental and translational work.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMAL1 Overexpression in the SCN Confers Protection Against Anxiety-Like Behaviors of Chronic Sleep Restricted-Mice.","authors":"Xiao Li, Xiya Wang, Lanyue Gao, Jiayu Wang, Honghong Yu, Tingting Du, Tian Hu, Qi Sun","doi":"10.1007/s12035-026-06249-1","DOIUrl":"10.1007/s12035-026-06249-1","url":null,"abstract":"<p><p>Children and adolescents globally experience inadequate sleep, which harms their cognitive functions and emotional regulation. The role of circadian clock genes in influencing the antioxidant and anti-inflammatory capabilities has been well-established. Previous studies reported that the impairment of neural activity within the suprachiasmatic nucleus (SCN) can lead to anxiety-like behaviors in mice. Our study was designed to explore the role of BMAL1 expression in SCN, which could be responsible for anxiety-like behaviors induced by chronic sleep restriction (SR) in young mice. Here, 5-week-old male mice were divided into four groups (CON^GFP, CON^AAV, SR^GFP, SR^AAV), with chronic sleep restriction applied to the SR^GFP group for 4 weeks using an automatic sleep restriction system. Meanwhile, the SR^AAV group received AAV injections overexpressing BMAL1 in the SCN before sleep restriction. Anxiety-like behaviors were assessed through the elevated cross-maze and three-box social experiments. In the SR^GFP group, there was a significant reduction in the number and duration of mice entering the open arm and the S2 chamber, which was further reduced by BMAL1 overexpression. Mechanistically, BMAL1 compensated for synaptic plasticity damage in the medial prefrontal cortex (mPFC) by upregulating the MAPK-induced inflammatory response, increasing the SOD level, and reducing the MDA level, ultimately restoring BDNF signaling. The study concludes that sleep restriction induces anxiety-like behaviors and impairs synaptic plasticity in the mPFC due to inflammation. Strengthening the molecular clock by BMAL1 overexpression in the SCN alleviated these effects during chronic sleep restriction.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles and Exosomes as Biomarkers in Huntington's Disease: Uncovering Pathogenic Insights and Pioneering Therapies.","authors":"Asma Vafadar, Dorsa Shaghaghian, Hossein Charami, Farzin Hadinia, Daryoush Didehdar, Ahmad Movahedpour, Sajad Ehtiati","doi":"10.1007/s12035-026-06205-z","DOIUrl":"10.1007/s12035-026-06205-z","url":null,"abstract":"<p><p>Huntington's disease (HD) is a neurodegenerative disorder caused by the expression of the mutant huntingtin protein (mHTT), characterized by a progressive decline in motor function, cognitive abilities, and psychiatric symptoms. Exosomes, a distinct class of small extracellular vesicles, have emerged as promising diagnostic biomarkers and potential therapeutic tools for early disease detection and intervention. This is largely attributed to their molecular stability, cell type-specific cargo, and potential to cross the blood-brain barrier under optimized structural or delivery conditions. Extracellular vesicles (EVs) exhibit disease-associated molecular modifications and can either exacerbate or alleviate proteotoxic stress in Huntington's disease. This review provides a comprehensive overview of the role of exosomes in HD, covering their biogenesis, functional characteristics, diagnostic potential, and therapeutic applications in neural degeneration associated with HD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ellagitannin Metabolite Urolithin D Ameliorates Cognitive Function and Behavioral Performance in Aging Mice Partially via AMPK/PGC-1α/SIRT3-Dependent Regulation of Mitophagy-Related Molecular Machinery.","authors":"Peng Chen, Yu Wang, Yingui Huang, Chenxi Yue, Jukai Dan, Jiexin Lei, Benhong Zhou","doi":"10.1007/s12035-026-06245-5","DOIUrl":"10.1007/s12035-026-06245-5","url":null,"abstract":"<p><p>This study aimed to investigate the protective effects of gut-derived urolithin D (Uro D) against neurodegenerative lesions in a D-galactose (D-gal)-induced chemical aging mouse model and its underlying molecular mechanisms. In vivo, mice received 8-week daily intraperitoneal injection of 150 mg/kg D-gal plus oral gavage of 50-150 mg/kg/day Uro D. The regulatory protein networks in related pathways and structural features of mitophagy-associated proteins were further explored. A D-gal-induced cellular stress model in HT22 neuronal cells was established to evaluate mitochondrial parameters, protein expression levels, and alterations in mitophagy-related molecular machinery. In vivo, Uro D treatment improved cognitive performance and behavioral impairment, reduced hippocampal pathology, preserved synaptic plasticity, and alleviated aging symptoms. Mechanistically, Uro D upregulated AMPK, PGC-1α, and mitochondrial SIRT3 expression to modulate mitochondrial functional activity. Uro D modulates mitophagy-associated signaling, accompanied by altered expression of Beclin1, LC3, P62, Parkin, and PINK1. Further in vitro experiments suggested that Uro D enhances mitochondrial integrity in cellular stress models. Progressive normalization of mitochondrial shape, oxidative stress, and calcium ion homeostasis contribute to the alleviation of pathological symptoms associated with aging. SIRT3 knockdown in HT22 cells increased mitochondrial damage and suppressed the activation of mitophagy-related molecular machinery. Further results from AMPK/PGC-1α inhibition and SIRT3 rescue experiments revealed that inhibition of AMPK or PGC-1α abolished the protective effects of Uro D, whereas SIRT3 overexpression alleviated D-gal-induced cellular abnormalities. Uro D partially triggers molecular changes consistent with mitophagy activation through the AMPK/PGC-1α/SIRT3 cascade, contributing to the mitigation of hippocampal neuronal injury and the improvement of learning and memory deficits in D-gal-induced aging mice.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Systematic Review of Stem Cell Secretome-Derived Exosomes for Neuropathic Pain: Therapeutic Mechanisms and Translational Potential.","authors":"Aidin Shahrezaei, Lili Dashti, Farinaz Nasirinezhad","doi":"10.1007/s12035-026-06225-9","DOIUrl":"10.1007/s12035-026-06225-9","url":null,"abstract":"<p><p>Neuropathic pain (NP) is a chronic disabling disorder with limited effective therapies. Exosomes isolated from the stem cell secretome have emerged as promising candidates because of their anti-inflammatory and neuroregenerative properties. This systematic review evaluated the mechanisms and translational potential of stem cell secretome-derived exosomes for NP. Following PRISMA 2020 guidelines, biomedical databases were searched from inception to Aug 2026. Eligible studies included preclinical and clinical investigations evaluating stem cell secretome-derived exosomes in NP models. Risk of bias was assessed using SYRCLE and RoB 2 or ROBINS-I. Because of substantial heterogeneity, a narrative synthesis was performed. Seventeen studies met the inclusion criteria, including 16 preclinical studies and one pilot clinical study. Most studies investigated mesenchymal stem cell secretome-derived exosomes and demonstrated reductions in pain-related behaviors across chronic constriction injury, diabetic peripheral neuropathy, and chemotherapy-induced peripheral neuropathy models. Therapeutic effects were associated with suppression of neuroinflammatory cytokines, inhibition of microglial activation, enhancement of neurotrophic signaling, and modulation of nuclear factor kappa B (NF-κB) and NOD-like receptor pyrin domain-containing 3 (NLRP3) pathways. The pilot clinical study suggested a favorable safety profile and potential benefit, although human evidence remains insufficient to establish clinical efficacy. Overall methodological quality was moderate, with heterogeneity in stem cell sources, exosome isolation methods, dosing strategies, administration routes, and outcome measures, precluding meta-analysis. Current evidence supports the biological plausibility of stem cell secretome-derived exosomes as emerging candidates for NP; however, randomized clinical trials and standardized vesicle characterization are required to establish efficacy and translational applicability.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Live-Cell Imaging System for the Identification of Pro- and Anti-Aggregatory α-Synuclein Modulators.","authors":"Tzukit Tal, Yael Almog, Ortal Iancu Cohen, Lihi Radomir, Dana Bar-On, Ianai Fishbein, Eran Meshorer","doi":"10.1007/s12035-026-06248-2","DOIUrl":"10.1007/s12035-026-06248-2","url":null,"abstract":"<p><p>α-Synuclein (αSyn) aggregation is a defining pathological feature of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA). However, existing in vitro methods to monitor αSyn aggregation often rely on endpoint assays that cannot distinguish monomeric from oligomeric species or capture early aggregation dynamics. Here, we implement an αSyn bimolecular fluorescence complementation (αSyn-BiFC) strategy in a stable human glial-derived cell system optimized for real-time, high-content analysis of early αSyn self-association events and their modulation. In this strategy, αSyn is fused to complementary fragments of the Venus fluorescent protein, enabling real-time visualization of αSyn-αSyn interactions during oligomer formation. Using U373 human astrocytoma cells, a scalable glial-derived cell line previously used in studies of MSA, we established both transient and stable αSyn-BiFC expression systems. We demonstrate that reconstituted Venus fluorescence correlates with pSer129 αSyn immunostaining, supporting the association of the BiFC signal with pathology-related αSyn assemblies. The model responded robustly to multiple stressors known to promote αSyn aggregation, including proteostasis disruption (leupeptin, MG132), ER stress (tunicamycin), and environmental toxins (rotenone), while iron, particularly Fe³⁺, also enhanced αSyn self-association. Furthermore, testing two small molecules previously shown to attenuate αSyn aggregation and pathology in vivo revealed a reduction in Venus fluorescence, consistent with reduced αSyn self-association and supporting the platform's utility for drug discovery screens. By providing a dynamic, sensitive, and physiologically relevant readout of early αSyn assemblies, the αSyn-BiFC model overcomes limitations of conventional assays and offers a scalable framework for mechanistic studies, compound screening, and integration into more disease-relevant neuronal and aging-enhanced models for future synucleinopathies research.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Artesunate Ameliorates Hippocampal LFP Abnormalities and Cellular Apoptosis in APP/PS1 Mice via a Mechanism Involving GHRH/PI3K/AKT Signaling.","authors":"Yue Jin, Xuewu Gong, Lei Shen, Meng Zhang, Ke Song, Hongbo Yao","doi":"10.1007/s12035-026-06250-8","DOIUrl":"10.1007/s12035-026-06250-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by progressive neurodegeneration and aberrant neural network activity. Artesunate (ART) has shown neuroprotective potential, but its effects on macroscopic hippocampal network dynamics and the underlying molecular mechanisms remain unclear. This study investigated the therapeutic efficacy and mechanisms of intranasal ART in APP/PS1 transgenic mice and Aβ_1-42-treated HT22 hippocampal neurons, integrating behavioral assays, multi-channel local field potential (LFP) recordings, ultrastructural analyses, and transcriptomics. In vivo, ART administration ameliorated cognitive deficits and mitigated macroscopic hippocampal LFP disruptions, manifested as an attenuation of the spectral power shift toward lower frequencies, reduced aberrant theta-gamma phase-amplitude coupling (PAC), and improved sharp-wave ripple (SWR) properties during resting states. Concurrently, ART reduced the number of TUNEL-positive cells and quantitatively preserved postsynaptic density (PSD) thickness and synaptic cleft width, alongside qualitative improvements in myelin sheath and mitochondrial morphology. Mechanistically, RNA-sequencing identified the neuroactive ligand-receptor interaction pathway as a prominent ART-responsive target, with growth hormone-releasing hormone (GHRH) emerging as a key candidate. In vitro pharmacological blockade revealed that ART's anti-apoptotic effects against Aβ toxicity depend on GHRH-R and subsequent PI3K/AKT cascade activation. This was accompanied by the inhibitory phosphorylation of GSK-3β, increased NF-κB p65 nuclear translocation, Bcl-2 upregulation, and caspase-3 inhibition. Collectively, these findings demonstrate that intranasal ART exerts sustained neuroprotective effects that preserve synaptic ultrastructure and ameliorate macroscopic network dysfunction in AD models. While the precise in vivo causality requires further validation, our in vitro data suggest that these cellular benefits are strongly associated with GHRH/PI3K/AKT signaling, highlighting ART as a promising therapeutic candidate for early AD.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low Dose NeuroD1 Delivery in Mouse TBI Models.","authors":"Isaac H Clark, Ansharah Khan, Christopher With, Zachary Roushdy, Dilmareth Natera-Rodriguez, Kevin Sun, Olivia Erlanson, Shaimaa Khedr, Walter C Low, Andrew W Grande","doi":"10.1007/s12035-026-06244-6","DOIUrl":"10.1007/s12035-026-06244-6","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) often results in serious neuronal tissue damage that can lead to progressive neurological impairment. NeuroD1, a transcription factor involved in neuronal differentiation, may be able to facilitate recovery post-TBI through the promotion of both neuroprotection and astrocyte-to-neuron reprogramming. The efficacy and optimal parameters for NeuroD1-based treatment, however, remain uncertain. This study investigated the effects of AAV-mediated NeuroD1 delivery in TBI mouse models, focusing on cellular reprogramming at low dosages. Dose response experiments revealed that lower viral doses provided the greatest transduction specificity. Notably, lower viral titers resulted in greater astrocyte-specific transduction whereas higher titers increased transduction in off-targets (neurons), potentially due to toxicity and/or leakage. Using these low dosages, our findings indicate that NeuroD1 treatment did not produce statistically significant structural restoration, nor did it greatly alter neuroinflammation measures; however, it did allow for functional improvement in beam walk performance, suggesting enhanced neurological recovery. Prospective studies should refine experimental conditions, incorporate a broader range of behavioral assessments, and explore combination therapies to enhance both functional and structural recovery. NeuroD1-based interventions remain a promising avenue for promoting functional improvement following TBI, although further research is required to drive these findings to clinical applications.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendrobium Officinale Polysaccharide Inhibits Ferroptosis and Ameliorates Cerebral Ischemia-Reperfusion Injury: Involvement of the Nrf2/GPX4 Signaling Pathway.","authors":"Xiaoxiao Li, Wenxin Xia, Caiyu Yang, Chenchen Xu, Xin Wang, Jianjian Dong, Yongsheng Han","doi":"10.1007/s12035-026-06208-w","DOIUrl":"10.1007/s12035-026-06208-w","url":null,"abstract":"<p><p>Ferroptosis, a critical pathological mechanism in ischemic stroke (IS), is activated during the early phase of cerebral ischemia-reperfusion injury (CI/RI). Dendrobium officinale polysaccharide (DOP), the primary bioactive component of Dendrobium officinale, exhibits diverse pharmacological activities, including antioxidant, anti-inflammatory, and immunomodulatory effects. DOP has been suggested to exert neuroprotective effects by inhibiting ferroptosis; however, its specific role and underlying mechanisms in IS-related ferroptosis remain unclear. In this study, in vivo and in vitro CI/RI models were established using middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. DOP was administered under a paradigm combining long-term pretreatment and short-term post-ischemic intervention, and its neuroprotective effects were evaluated. In MCAO/R mice, DOP significantly alleviated neurological deficits, reduced the cerebral infarct volume, and mitigated neuronal damage. These effects were associated with decreased Fe²⁺ accumulation and lipid peroxidation, ameliorated mitochondrial impairment, and upregulated the expression of key ferroptosis-related proteins, including nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4). Consistent with in vivo findings, DOP enhanced the viability of HT-22 cells subjected to OGD/R, decreased reactive oxygen species, and restored the mitochondrial membrane potential, accompanied by increased Nrf2 and GPX4 expression. Notably, knockdown of Nrf2 attenuated GPX4 expression and diminished the protective effects of DOP. Collectively, these findings suggest that DOP exerts neuroprotective effects against CI/RI, at least in part, by inhibiting ferroptosis through the Nrf2/GPX4 signaling pathway, supporting its potential role in preventive and early-stage intervention strategies for ischemic stroke.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}