Molecular Neurobiology最新文献

{"title":"Correction to: MiR‑17‑5p Mediates the Effects of ACE2‑Enriched Endothelial Progenitor Cell‑Derived Exosomes on Ameliorating Cerebral Ischemic Injury in Aged Mice.","authors":"Qunwen Pan, Yan Wang, Jinhua Liu, Xiaojuan Jin, Zhi Xiang, Suqing Li, Yumeng Shi, Yanfang Chen, Wangtao Zhong, Xiaotang Ma","doi":"10.1007/s12035-026-06261-5","DOIUrl":"https://doi.org/10.1007/s12035-026-06261-5","url":null,"abstract":"","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182041","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":"NAD+ Attenuates Neuroinflammation in Ischemic Stroke by Suppressing the cGAS- STING Pathway via Mitochondrial Homeostasis Restoration.","authors":"Sijia Jiang, Bo Liao, Guiping Wang, Rui Sheng, Chong Han, Zhi Jiang, ShanYao Pan, Chu Wu, Guoqiang Liang, Yongming Zhu, Ming Cheng, Feiyan Zhao, Zhiyin Jiang, Xuyi Yao, Zhenghong Qin, Yaping Huai, Yiqing Lu, Weiwei Yang, Jie Bao, Qing Zhang, Gang Zhao, Jiao Deng, Zhi Gang Lv, Junchao Wu, Li Luo, Yuanyuan Qin","doi":"10.1007/s12035-026-06257-1","DOIUrl":"10.1007/s12035-026-06257-1","url":null,"abstract":"<p><p>Stroke remains one of the leading causes of death and disability worldwide, with neuroinflammation playing a critical role in its pathogenesis. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a major driver of innate immune responses activated by endogenous DNA, including mitochondrial DNA (mtDNA), and contributes significantly to post-ischemic neuroinflammation. Nicotinamide adenine dinucleotide (NAD⁺), a vital metabolic coenzyme, has demonstrated anti-inflammatory potential in various diseases, including stroke; however, its specific role in regulation of neuroinflammation following stroke remains unclear. In this study, we examined the protective effects of NAD⁺ against ischemic stroke and explored its role in modulating cGAS-STING-mediated neuroinflammatory responses. Utilizing a transient middle cerebral artery occlusion/reperfusion mouse model and an oxygen-glucose deprivation/reoxygenation BV2 microglia model, we observed that NAD⁺ treatment significantly reduced infarct volume and brain edema, and improved neurological outcomes. NAD⁺ reduced the levels of pro-inflammatory cytokines and facilitated the polarization of microglia from pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This effect was associated with the inhibition of cGAS-STING-TBK1 signaling pathway activation. Pharmacological inhibition or genetic knockdown of STING largely abrogated the anti-inflammatory effects of NAD⁺ in BV2 microglia, indicating a STING-dependent mechanism. Furthermore, NAD⁺ restored mitochondrial respiratory function and reduced cytoplasmic mtDNA leakage, suggesting that the improvement of mitochondrial homeostasis may underlie the suppression of cGAS-STING-TBK1 signaling pathway by NAD⁺. Our findings indicate that NAD⁺ alleviates neuroinflammation following brain ischemia/reperfusion injury by regulating mitochondrial homeostasis and attenuates the cGAS-STING-TBK1 signaling pathway activation in microglia, thereby providing new therapeutic insights for ischemic stroke.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182326","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":"Oculopharyngeal Muscular Dystrophy: From Molecular Pathogenesis to Gene Therapy.","authors":"Claudia Alberti, Delia Gagliardi, Dario Ronchi, Michela Ripolone, Laura Napoli, Maurizio Moggio, Giacomo Pietro Comi, Stefania Corti","doi":"10.1007/s12035-026-06251-7","DOIUrl":"10.1007/s12035-026-06251-7","url":null,"abstract":"<p><p>Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, autosomal dominant muscular dystrophy caused by a trinucleotide GCN repeat expansion in the PABPN1 gene on chromosome 14q11.2. The disease is clinically characterised by progressive ptosis, dysphagia, and proximal limb weakness, with onset typically between the fifth and sixth decades. OPMD affects approximately 1:100,000 individuals in Europe, with substantially higher prevalence in specific founder populations, reaching 1:600 among Bukharan Jews and 1:1,000 in French Canadians. The expanded polyalanine tract in PABPN1 promotes protein misfolding and formation of tubulofilamentous intranuclear inclusions, the histopathological hallmark of the disease. Pathogenic mechanisms involve a complex interplay of gain-of-function toxicity from aggregated mutant PABPN1, loss-of-function effects due to reduced polyadenylation efficiency, and dominant-negative impairment of poly(A) tail elongation, mRNA processing and nuclear mRNA export. Recent advances in proximity proteomics have refined the understanding of how the alanine expansion destabilises PABPN1 and alters its interactome. Diagnosis relies on molecular genetic testing of the PABPN1 GCN repeat expansion, while PABPN1 immunofluorescence on muscle biopsy provides a highly sensitive and specific ancillary tool. Current management remains symptomatic, including cricopharyngeal myotomy for dysphagia and surgical correction of ptosis. The therapeutic landscape is evolving, with BB-301, an adeno-associated virus-based gene therapy employing a DNA-directed RNA interference (ddRNAi) silence-and-replace strategy, currently in a Phase 1b/2a clinical trial. This review provides a comprehensive synthesis of OPMD, spanning historical background, molecular genetics, pathophysiology, clinical presentation, diagnostic approach, and the emerging therapeutic pipeline.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182344","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":"Metallothionein-Related Findings in Autism Spectrum Disorder: A Systematic Review and Targeted Quantitative Synthesis of Human Studies.","authors":"Geir Bjørklund","doi":"10.1007/s12035-026-06255-3","DOIUrl":"10.1007/s12035-026-06255-3","url":null,"abstract":"<p><p>Metallothioneins (MTs) are cysteine-rich proteins that regulate zinc (Zn) and copper (Cu) homeostasis, bind toxic metals, and contribute to redox control. Disturbed trace-element status, oxidative stress, gastrointestinal disease, and immune alterations have been reported in autism spectrum disorder (ASD), raising the question of whether MT biology is altered in this condition. Systematic searches of PubMed, Embase, Web of Science Core Collection, Scopus, Cochrane CENTRAL, and APA PsycINFO were updated on 5 September 2026. Studies directly measuring circulating MT protein, MT isoform mRNA, or anti-MT immunoglobulin G (IgG) antibodies in individuals with ASD, their first-degree relatives, or both were eligible. The review followed PRISMA 2020. Nine reports met the eligibility criteria, comprising eight primary reports and one secondary analysis. Study-level standardized mean differences, risk ratios, and odds ratios were calculated when sufficient published data were available. No pooled meta-analysis was performed because sufficiently comparable datasets were unavailable; otherwise, findings were synthesized narratively. Serum MT protein did not differ significantly between ASD and controls in one study, whereas one small, selected gastrointestinal cohort reported more participants above a study-defined high-MT threshold. In an uncontrolled Zn supplementation study, serum MT-1A increased together with higher serum Zn and lower Cu, but the absence of a concurrent control group precluded causal attribution. Five primary reports assessed MT gene expression, with higher, lower, null, and internally inconsistent findings across different MT isoforms and blood-derived samples; no reproducible ASD-associated transcriptional pattern was identified. Anti-MT antibody findings were also inconsistent across familial, gastrointestinal, and ASD-control comparisons. Across eight primary human reports, MT-related findings in ASD were inconsistent across cohorts, biological matrices, and clinical contexts. Current evidence does not establish a consistent ASD-associated alteration of the MT system, an ASD-specific anti-MT antibody response, or a validated MT biomarker. It also does not determine whether gastrointestinal phenotype, trace-element status, redox biology, immune-related factors, or other variables explain the observed between-study differences. Larger, independently replicated studies using standardized MT measurements and well-characterized populations are required.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182324","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":"Ayahuasca Impairs Fear Memory Reconsolidation and Promotes Rapid Structural Plasticity in the Hippocampus and Prelimbic Cortex.","authors":"Daiane Momo Daneluz, Alana Sueli Dos Santos, Silvana Regina de Melo, Rúbia Maria Weffort de Oliveira, Cristina Aparecida Jark Stern","doi":"10.1007/s12035-026-06264-2","DOIUrl":"10.1007/s12035-026-06264-2","url":null,"abstract":"<p><p>Psychedelic drugs promote rapid neuroplasticity in brain regions affected by trauma exposure, such as the prelimbic (PL) cortex and the dorsal hippocampus (DH), being investigated as potential treatments for posttraumatic stress disorder. Ayahuasca (Aya) contains N,N-dimethyltryptamine, a classic psychedelic. Our previous work showed that Aya reduces fear expression by impairing fear memory reconsolidation. We hypothesized that Aya administration during reconsolidation induces neuroplastic changes in DH and PL cortex associated with its behavioral effects. Adult male Wistar rats underwent contextual fear conditioning and received Aya (60 mg/kg, oral gavage) or H₂O (vehicle) 20 min before or 3 h after fear memory retrieval. To confirm the reconsolidation-impairing effect of Aya, animals were re-exposed to the conditioned context 24 h later. Structural plasticity was assessed 24 h after retrieval and drug administration by Golgi-Cox staining of the DH and the PL cortex. Neurogenesis was evaluated 10 days later by doublecortin (DCX) immunohistochemistry of dentate gyrus. Aya significantly reduced freezing behavior, confirming the reconsolidation-impairing effect. This outcome was accompanied by increased dendritic spine density in the CA1, CA3, and dentate gyrus regions of the DH, as well as in the PL cortex. In the PL cortex, Aya altered dendritic branching and length depending on the timing of administration. In contrast, Aya did not affect adult hippocampal neurogenesis. Together, these findings suggest that rapid synaptic remodeling in the DH and PL cortex, rather than changes in adult hippocampal neurogenesis, is associated with the reconsolidation-impairing effect of Aya.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168157","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":"Integrative Transcriptomic and Interactome Analyses Prioritize Candidate Genes for Alzheimer's Disease.","authors":"Giovanni Monteiro Maglio, Nicolly Clemente de Melo, Lucas Miguel de Carvalho","doi":"10.1007/s12035-026-06258-0","DOIUrl":"https://doi.org/10.1007/s12035-026-06258-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized by complex molecular alterations and diverse cognitive, behavioral, and neuropsychiatric manifestations. Although transcriptomic studies have identified several pathways associated with AD, the integration of molecular signatures with disease-related phenotype annotations and pathological aging remains incompletely understood. Therefore, this study aimed to integrate transcriptomic profiling, protein-protein interaction (PPI) network analysis, pathological aging assessment, and curated clinical phenotype annotations to prioritize candidate molecular signatures associated with AD. Differential expression analyses and network-based approaches were applied to publicly available transcriptomic datasets derived from distinct brain regions. Candidate genes and pathways were prioritized through interactome reconstruction, functional enrichment analyses, cluster-based analyses, and independent validation in an external dataset. In addition, transcriptomic signatures were integrated with curated clinical phenotype annotations using a knowledge-based gene overlap strategy. The analysis identified molecular signatures associated with neuroinflammatory signaling, synaptic dysfunction, endocytosis, and pathological aging. Pathways related to MAPK, PI3K/Akt, NF-κB, and TGF-β1 signaling emerged as candidate dysregulated pathways in AD. Comparative analyses of physiological aging and the AD aging comparison enabled the prioritization of candidate genes potentially more closely associated with the AD condition than with aging alone, including FOS and TAB2. Independent validation reinforced the reproducibility of several prioritized genes, including GFAP, CXCR4, CCL2, HSPA1A, FCGR2A, TLR2, CD44, TLR4, FOS, TAB2, CDC42, and SH3GL2. Integration with curated clinical phenotype annotations suggested partially overlapping molecular signatures across neuropsychiatric and cognitive phenotype annotations in AD. Together, these findings demonstrate the utility of integrative bioinformatics approaches for prioritizing candidate genes, pathways, and molecular signatures associated with AD. This systems-level framework may contribute to future mechanistic studies aimed at understanding the molecular heterogeneity of AD and its associated phenotypic complexity.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167874","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":"The Gut Microbiota-Epilepsy Axis: Bibliometric Trends, Mechanistic Insights, and Microbiota-Targeted Next-Generation Therapeutic Opportunities.","authors":"Ayyaz Khan, Zakir Ullah, Muhammad Siraj, Sonia Younas, Shahid Wahab, Abdul Waris, Seong-Tshool Hong","doi":"10.1007/s12035-026-06227-7","DOIUrl":"https://doi.org/10.1007/s12035-026-06227-7","url":null,"abstract":"<p><p>Epilepsy is a complex neurological disorder with diverse underlying causes. Growing evidence suggests that gut dysbiosis may promote epileptogenesis by disrupting short-chain fatty acids, tryptophan-kynurenine metabolism, immune signaling, and neuronal excitability. In this review, we combine findings from human and animal studies to explain how gut dysbiosis may influence seizures through the gut-brain axis. We highlight emerging and less-discussed mechanisms, including vagus nerve signaling, microbial amyloids, bacterial extracellular vesicles (BEVs), the queuosine salvage pathway, and multi-kingdom microbiota interactions. We also summarize microbiota profiling studies and describe dysbiosis patterns linked to seizure. To support translation, we propose a peri-ictal multi-omics strategy for biomarker discovery. This includes standardized sampling and integration of metagenomics, metabolomics, and host transcriptomics. In addition, our bibliometric analysis further shows rapidly growing global interest in this topic. Recent studies increasingly focus on the gut-brain axis, ketogenic diet, and inflammation-driven mechanisms. Finally, we outline both established approaches and emerging next-generation microbiome-based therapeutic strategies, including SCFA-restoring synbiotics, engineered psychobiotics, bacteriophage therapy, and AI-guided personalization. These advances highlight the microbiota as modifiable target for adjunctive epilepsy management and provide a translational roadmap for future mechanistically informed research and clinical interventions.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166992","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":"Neuronal IL-18 Signaling in the Medial Habenula Contributes to Schizophrenia-Like Behavioral Deficits via ERK-Associated BDNF Suppression.","authors":"Dongjie Sun, Chi Zhang, Menghui Hou, Hua Zhao","doi":"10.1007/s12035-026-06253-5","DOIUrl":"10.1007/s12035-026-06253-5","url":null,"abstract":"<p><p>Current antipsychotics for schizophrenia (SCZ) are notably ineffective against the debilitating cognitive and negative symptoms, creating a major therapeutic gap. Neuroinflammation in the medial habenula (MHb) is implicated in SCZ; however, the underlying cell-type-specific mechanisms remain unknown. This study aimed to determine whether pathologically elevated neuronal interleukin-18 (IL-18) in the MHb contributes to schizophrenia-like behavioral abnormalities through ERK-associated downregulation of brain-derived neurotrophic factor (BDNF). Utilizing an MK-801-treated rat model, we adopted a multi-modal approach. Single-cell RNA sequencing was used to identify the cellular origin of pathological IL-18. We then combined neuron-specific viral manipulations to test functional involvement, chemogenetics to manipulate MHb neuronal activity, and ex vivo electrophysiology to measure neuronal excitability. Finally, targeted pharmacological interventions were used to test the functional contribution of this signaling pathway. MHb neurons exhibited marked hypoactivity and pathological changes in MK-801-treated rats. Single-cell RNA sequencing and histological analyses indicated that MHb neurons are the predominant cellular source of the pathological IL-18 signal in this model. Functionally, neuron-specific IL-18 overexpression was sufficient to induce schizophrenia-like behavioral abnormalities, whereas its knockdown ameliorated negative-like and cognitive deficits. Mechanistically, our data support a model in which elevated neuronal IL-18 is associated with ERK overactivation, reduced BDNF expression, and neuronal hypoactivity. Furthermore, pharmacological inhibition of the ERK pathway in the MHb ameliorated deficits at the molecular (BDNF), cellular (neuronal firing), and behavioral levels. Our findings support a neuron-centered IL-18/ERK/BDNF signaling framework in the MHb that contributes to schizophrenia-like pathological changes in this model and warrants further preclinical investigation as a potential target for cognitive and negative symptoms relevant to schizophrenia.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149186","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":"Zbtb18 Deficiency Impairs the Hippocampal Development and Neurite Growth.","authors":"Yuzhuo Zhou, Yiyuli Tang, Cheng Peng","doi":"10.1007/s12035-026-06254-4","DOIUrl":"10.1007/s12035-026-06254-4","url":null,"abstract":"<p><p>Previous studies of the transcription factor Zbtb18 have primarily focused on its role in cortical development, whereas its function during hippocampal development remains poorly understood. In this study, we investigated the role of Zbtb18 in mouse hippocampal development using histological, transcriptomic, and functional approaches. Immunostaining demonstrated that Zbtb18 was partially overlapped with the neural progenitor marker Pax6, intermediate progenitor marker Tbr2, postmitotic neuronal marker Tbr1, and neuronal marker NeuN in the hippocampal primordium from embryonic day 13.5. Loss of Zbtb18 was associated with pronounced hippocampal malformations, including Dentate Gyrus disorganization and altered cellular architecture. Single-nucleus RNA sequencing at embryonic day 18.5 suggested alterations in neuronal composition within the Cornu Ammonis and Dentate Gyrus regions, accompanied by increased Prox1 expression and abnormal progenitor cell proliferation. Pathway analyses identified transcriptional alterations associated with neurogenesis, neuronal differentiation, neuronal morphogenesis, and cAMP signaling. Consistent with these findings, primary hippocampal neurons derived from Zbtb18-deficient embryos exhibited reduced longest neurite length and total neurite length in vitro. Pharmacological activation of cAMP signaling with forskolin partially improved neurite growth in Zbtb18-deficient neurons. Together, these findings suggest that Zbtb18 regulates hippocampal development and neurite growth, in which the cAMP signaling pathway is involved in the neuronal morphological defect.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137645","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":"High-Frequency Repetitive Transcranial Magnetic Stimulation Attenuates Post-Stroke Brain Fibrosis by Increasing Brain-Derived Estrogen Levels: A Dual-Tracer PET/CT Study.","authors":"Yuting Cao, Peipei Tang, Dan Feng, Hankuan He, Han Wu, Yang Liu, Jinfeng Tian, Kongzhen Hu, Yuhua Zhong","doi":"10.1007/s12035-026-06259-z","DOIUrl":"10.1007/s12035-026-06259-z","url":null,"abstract":"<p><p>Fibrotic scar formation after ischemic stroke limits neuroplasticity and functional recovery. While estradiol (E2) exerts anti-fibrotic effects, the mechanisms by which high-frequency repetitive transcranial magnetic stimulation (rTMS) promotes post-stroke recovery remain poorly understood. We investigated whether rTMS attenuates post-ischemic brain fibrosis via aromatase-dependent local E2 synthesis. Male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion received high-frequency rTMS starting post-stroke day 3. Fibrosis and metabolism were evaluated using longitudinal dual-tracer [¹⁸F]AlF-FAPI-42 and [¹⁸F]FDG PET/CT on days 3 and 14, alongside histological and biochemical assessments. The aromatase inhibitor letrozole was used to probe mechanistic dependence. Additionally, we retrospectively analyzed dual-tracer PET/CT data from 10 ischemic stroke patients. In rats, rTMS significantly reduced [¹⁸F]AlF-FAPI-42 uptake, decreased collagen deposition and fibrotic marker expression, increased [¹⁸F]FDG uptake, and improved neurological outcomes. rTMS also upregulated aromatase expression and elevated peri-infarct E2 levels; these anti-fibrotic and metabolic benefits were no longer observed under letrozole treatment. Brain E2 levels correlated negatively with [¹⁸F]AlF-FAPI-42 uptake and positively with motor performance. Corroborating the preclinical model, clinical imaging revealed elevated [¹⁸F]AlF-FAPI-42 uptake in the ischemic hemisphere of patients, which was inversely associated with [¹⁸F]FDG uptake. These findings demonstrate that high-frequency rTMS attenuates post-stroke fibrosis and promotes metabolic recovery partly through aromatase-dependent elevation of local E2. Furthermore, dual-tracer [¹⁸F]AlF-FAPI-42/[¹⁸F]FDG PET provides a novel, non-invasive method for monitoring fibrosis-metabolism coupling. The clinical findings highlight the translational relevance of this relationship, suggesting that tracking fibrotic remodeling could guide post-stroke rehabilitation.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137608","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}