Molecular and Cellular Neuroscience最新文献

{"title":"Olfactory bulb interneurons – The developmental timeline and targeting defined by embryonic neurogenesis","authors":"Natalie J. Spence ,&nbsp;Eduardo Martin-Lopez ,&nbsp;Kimberly Han ,&nbsp;Marion Lefèvre ,&nbsp;Nathaniel W. Lange ,&nbsp;Bowen Brennan ,&nbsp;Charles A. Greer","doi":"10.1016/j.mcn.2025.104007","DOIUrl":"10.1016/j.mcn.2025.104007","url":null,"abstract":"<div><div>The generation of mouse olfactory bulb (OB) interneurons (INs) is initiated in the embryo but continues throughout life. It is generally agreed that OB INs generated postnatally affect the connectivity of the OB, depending on the timeline of neurogenesis. Here, we focused on OB INs generated embryonically, which have generally received less attention than those generated in the adult. Birthdates of embryonic INs were differentiated by maternal injections of thymidine analogs and their final destinations and phenotypes in the OB analyzed by immunohistochemistry. We found that the first embryonic INs were generated at embryonic day 10 (E10) and continued through the entire embryonic development. Analysis in adult tissues showed that embryonic INs were retained and were distributed across all layers of the OB. Interestingly, an initial lateral preference in cell density was seen in INs generated during E11–E13. Although INs are broadly distributed in the OB, we found that within the granule cell layer (GCL), OB INs distributed mostly in the superficial GCL. Immunostaining for calbindin, parvalbumin, tyrosine hydroxylase, 5T4 and calretinin were lacking co-expression with thymidine analogs labeled cells, suggesting that maturation of embryonic INs occurred slowly following birth. We studied the embryonic neuroblasts migration and differentiation by labeling IN progenitor cells in the lateral ganglionic eminence using in utero electroporation. We found that IN neuroblasts reached the primordial OB as early as E13 and began to differentiate apical dendrites by E15, which extended into the developing external plexiform layer. We established E16 as the embryonic stage at which the prototypical chain of migrating neuroblasts denoting the embryonic rostral migratory stream (RMS) was visible. Collectively, our data highlight the importance of studying OB INs in isolated time windows to better understand the formation of circuits that define the olfactory system function.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104007"},"PeriodicalIF":2.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-based therapeutics: Advancing drug delivery for neurodegenerative diseases","authors":"Sakshi Rai ,&nbsp;Suman Kumar Ray ,&nbsp;Jagat R. Kanwar ,&nbsp;Sukhes Mukherjee","doi":"10.1016/j.mcn.2025.104004","DOIUrl":"10.1016/j.mcn.2025.104004","url":null,"abstract":"<div><div>Neurodegenerative disorders include Parkinson's disease, spinal cord injury, multiple sclerosis and Alzheimer's disease, cause gradual neuronal loss, protein misfolding, and accumulation, resulting in severe cognitive and movement deficits. Despite substantial study, therapeutic interventions are hampered by the blood-brain barrier, which prevents medication distribution to the central nervous system. Traditional pharmaceutical methods, such as small compounds, peptides, and inhibitors, have shown minimal effectiveness in addressing this obstacle. Exosomes are nanoscale membrane-bound vesicles that are primarily engaged in intercellular communication. They have the inherent capacity to cross the blood-brain barrier, which allows them to be used as medication delivery vehicles for brain illness therapy. Exosomes may be derived from a variety of cells like microglia, astrocytes identified according to origin, increasing their flexibility as drug delivery vehicles. Advanced engineering approaches optimise exosomes for tailored distribution across the blood-brain barrier, paving the path for novel neurodegenerative disease treatments. This review discusses the promise of exosome-based drug delivery, focussing on their composition, biogenesis, engineering, and applications in treating central nervous system illnesses, eventually overcoming the unmet hurdles of crossing the blood-brain barrier.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104004"},"PeriodicalIF":2.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK-3β dysregulation in aging: Implications for tau pathology and Alzheimer's disease progression","authors":"A. Rekha ,&nbsp;Muhammad Afzal ,&nbsp;M. Arockia Babu ,&nbsp;Soumya V. Menon ,&nbsp;Deepak Nathiya ,&nbsp;S. Supriya ,&nbsp;Shakti Bedanta Mishra ,&nbsp;Sofia Gupta ,&nbsp;Kavita Goyal ,&nbsp;Mohit Rana ,&nbsp;Haider Ali ,&nbsp;Mohd Imran","doi":"10.1016/j.mcn.2025.104005","DOIUrl":"10.1016/j.mcn.2025.104005","url":null,"abstract":"<div><div>The role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Alzheimer's disease (AD) is critical for linking amyloid-beta (Aβ) and Tau pathology. The activity of GSK-3β is dysregulated in the regulation of Tau hyperphosphorylation, formation of neurofibrillary tangles (NFTs), and production of Aβ by modulating amyloid precursor protein (APP) processing. This review discusses the mechanisms controlling GSK-3β dysregulation in aging and its influence on AD progression, focusing on the role of neuroinflammation, oxidative stress, and defective signaling pathways, including PI3K/Akt and Wnt. Critical analysis is presented for therapeutic strategies targeting GSK-3β using natural compounds (e.g., curcumin, geniposide) and emerging approaches such as TREM2 modulation and miRNA therapies. In preclinical models, these interventions promise to reduce Tau hyperphosphorylation and Aβ burden, along with associated neurodegeneration. Nevertheless, achieving selective GSK-3β inhibition and optimizing drug delivery are still critical barriers to clinical translation. This review underscores the central role of GSK-3β in AD pathogenesis to highlight its potential as a multifaceted therapeutic target of an innovative strategy for treating this complex neurodegenerative disease.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104005"},"PeriodicalIF":2.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interrogating mediators of single-cell transcriptional changes in the acute damaged cerebral cortex: Insights into endothelial-astrocyte interactions","authors":"Caroline de Jager ,&nbsp;Eman Soliman ,&nbsp;Michelle H. Theus","doi":"10.1016/j.mcn.2025.104003","DOIUrl":"10.1016/j.mcn.2025.104003","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) induces complex cellular and molecular changes, challenging recovery and therapeutic development. Although molecular pathways have been implicated in TBI pathology, the cellular specificity of these mechanisms remains underexplored. Here, we investigate the role of endothelial cell (EC) EphA4, a receptor tyrosine kinase receptor involved in axonal guidance, in modulating cell-specific transcriptomic changes within the damaged cerebral cortex. Utilizing single-cell RNA sequencing (scRNA-seq) in an experimental TBI model, we mapped transcriptional changes across various cell types, with a focus on astrocytes and ECs. Our analysis reveals that EC-specific knockout (KO) of EphA4 triggers significant alterations in astrocyte gene expression and shifts predominate subclusters. We identified six distinct astrocyte clusters (C0–C5) in the damaged cortex including as C0-<em>Mobp</em>/<em>Plp1</em>+; C1-<em>Slc1a3</em>/<em>Clu</em>+; C2-<em>Hbb-bs</em>/<em>Hba-a1</em>/<em>Ndrg2</em>+; <em>C3-GFAP</em>/<em>Lcn2+</em>; C4-<em>Gli3</em>/<em>Mertk+</em>, and C5-<em>Cox8a+</em>. We validate a new Sox9+ cluster expressing Mertk and Gas, which mediates efferocytosis to facilitate apoptotic cell clearance and anti-inflammatory responses. Transcriptomic and CellChat analyses of EC-KO cells highlights upregulation of neuroprotective pathways, including increased amyloid precursor protein (<em>APP</em>) and <em>Gas6</em>. Key pathways predicted to be modulated in astrocytes from EC-KO mice include oxidative phosphorylation and FOXO signaling, mitochondrial dysfunction and ephrin B signaling. Concurrently, metabolic and signaling pathways in endothelial cells—such as ceramide and sphingosine phosphate metabolism and NGF-stimulated transcription—indicate an adaptive response to a metabolically demanding post-injury hypoxic environment. These findings elucidate potential interplay between astrocytic and endothelial responses as well as transcriptional networks underlying cortical tissue damage.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 104003"},"PeriodicalIF":2.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RBM15 relies on m6A modification to inhibit UBE2C, alleviating hippocampal neuronal injury by limiting microglial inflammation","authors":"Yuehong Wan,&nbsp;Qin Kang,&nbsp;Ji Zhang,&nbsp;Canru Yu,&nbsp;Susu Fang,&nbsp;Dongqin Zou,&nbsp;Wen Chai","doi":"10.1016/j.mcn.2025.103996","DOIUrl":"10.1016/j.mcn.2025.103996","url":null,"abstract":"<div><h3>Background</h3><div>Microglia are strongly implicated in the development and progression of epilepsy, yet their impact on pathology remains unclear. This study aimed to explore the effects of ubiquitin-conjugating enzyme 2C (UBE2C) m6A methylation on microglial activation and neuronal injury in epilepsy.</div></div><div><h3>Methods</h3><div>A mouse model of pilocarpine-induced status epilepticus was constructed, and an in vitro system of HT22 hippocampal neurons was induced with Mg²⁺-free medium and cocultured with BV2 cells. The secretion of TNF-α, IL-6 and iNOS from BV2 cells was measured via qRT–PCR and ELISA. CCK-8 and flow cytometry were performed to verify cell viability and apoptosis. RNA degradation, RIP and Me-RIP assays were performed.</div></div><div><h3>Results</h3><div>RBM15 levels were decreased, whereas UBE2C levels were increased in the hippocampi of epileptic mice. Silencing UBE2C or overexpressing RBM15 suppressed the release of inflammatory cytokines (TNF-α and IL-6) and the M1 microglia activation marker iNOS in Mg²⁺-free BV2 cells, thereby limiting damage to hippocampal injured neurons. Mechanistically, RBM15 bound to UBE2C mRNA and decreased its stability via m6A methylation. Additionally, RBM15 inhibited the inflammatory activation of BV2 and HT22 neuron injury by inhibiting UBE2C.</div></div><div><h3>Conclusion</h3><div>The increase in UBE2C m6A modification induced by RBM15 upregulation inhibits hippocampal neuron damage through the suppression of microglial inflammation, providing important clues and potential targets for novel therapeutics for epilepsy.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 103996"},"PeriodicalIF":2.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P2X7 receptor augments kainic acid-induced nitrosative stress by abrogating GS-HSP25-mediated iNOS inhibition and GSH synthesis in the mouse hippocampus","authors":"Ji-Eun Kim,&nbsp;Duk-Shin Lee,&nbsp;Su Hyeon Wang,&nbsp;Tae-Cheon Kang","doi":"10.1016/j.mcn.2025.103995","DOIUrl":"10.1016/j.mcn.2025.103995","url":null,"abstract":"<div><div>Glutathione (GSH) and heat shock protein 25 (HSP25) reciprocally regulate each other, which maintain redox homeostasis. Since P2X7 receptor (P2X7R) regulates GSH biosynthesis and HSP25 induction, the present study was conducted to explore the role of P2X7R in the reciprocal regulation between HSP25 and GSH in response to kainic acid (KA)-induced nitrosative stress and the related signal pathways, which are largely unknown. The present data demonstrate that <em>P2X7R</em> deletion attenuated KA-induced reductions in total GSH level and nuclear factor-erythroid 2-related factor 2 (Nrf2) intensity/nuclear translocation in astrocytes. <em>P2X7R</em> ablation increased Nrf2 intensity/nuclear translocation in microglia following KA treatment. <em>P2X7R</em> deletion also ameliorated KA-induced inducible nitric oxide synthase (iNOS) and <em>S</em>-nitrosylated-cysteine (SNO-Cys) inductions in microglia and astrocytes. However, <em>P2X7R</em> ablation could not affect KA-induced nuclear Nrf2 translocation and SNO-Cys production in CA3 neurons. Furthermore, <em>P2X7R</em> ablation mitigated <em>S</em>-nitrosylations of glutamine synthase (GS) and alanine-serine-cysteine transporter 2 (ASCT2) induced by KA. <em>HSP25</em> knockdown increased GSH consumption, astroglial iNOS level and <em>S</em>-nitrosylations of GS and ASCT2, but decreased Nrf2 intensity/nuclear translocation in astrocytes of <em>P2X7R</em>^{<em>−/−</em>} mice following KA injection. These findings indicate that P2X7R facilitated iNOS upregulation by inhibiting HSP25 induction and nuclear Nrf2 translocation in astrocytes, which augmented nitrosative stress-mediated reduction in GSH biosynthesis in response to KA. Therefore, our data suggest that the targeting of P2X7R-Nrf2-iNOS-GS-HSP25 pathway may be required for the maintenance of GSH-mediated redox homeostasis against nitrosative stress, which would prevent the progression of undesirable consequences from seizures and neuroinflammation.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"133 ","pages":"Article 103995"},"PeriodicalIF":2.6,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A microglial kinase ITK mediating neuroinflammation and behavioral deficits in traumatic brain injury","authors":"Ruqayya Afridi ,&nbsp;Anup Bhusal ,&nbsp;Seung Eun Lee ,&nbsp;Eun Mi Hwang ,&nbsp;Hoon Ryu ,&nbsp;Jong-Heon Kim ,&nbsp;Kyoungho Suk","doi":"10.1016/j.mcn.2025.103994","DOIUrl":"10.1016/j.mcn.2025.103994","url":null,"abstract":"<div><div>Microglia-mediated neuroinflammation has been implicated in the neuropathology of traumatic brain injuries (TBI). Recently, the expression of interleukin-2-inducible T-cell kinase (ITK) has been detected in brain microglia, regulating their inflammatory activities. However, the role of microglial ITK in TBI has not been investigated. In this study, we demonstrate that ITK expression and activation are upregulated in microglia following an injury caused by controlled cortical impact (CCI) – a mouse model of TBI. Pharmacological inhibition of ITK protein or knockdown of microglial ITK gene expression using adeno-associated virus mitigates neuroinflammation and improves neurological outcomes in the CCI model. Additionally, ITK mRNA expression was found to be increased in the brains of patients with chronic traumatic encephalopathy. An ITK inhibitor reduced the activation of inflammatory responses in both human and mouse microglia in vitro. Collectively, these results suggest that microglial ITK plays a pivotal role in neuroinflammation and mediating behavioral deficits following TBI. Thus, targeting the signaling pathway of microglial ITK may exert protective effects by alleviating neuroinflammation associated with TBI.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103994"},"PeriodicalIF":2.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling","authors":"Xuan Liu ,&nbsp;Tianjiao Li ,&nbsp;Xinya Tu,&nbsp;Mengying Xu,&nbsp;Jianwu Wang","doi":"10.1016/j.mcn.2025.103992","DOIUrl":"10.1016/j.mcn.2025.103992","url":null,"abstract":"<div><div>Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca²⁺ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca²⁺ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca²⁺ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca²⁺ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103992"},"PeriodicalIF":2.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying potential genes driving ferroptosis in the substantia nigra and dopaminergic neurons in Parkinson's disease","authors":"Ardra Chakrabarti,&nbsp;Sonia Verma","doi":"10.1016/j.mcn.2025.103993","DOIUrl":"10.1016/j.mcn.2025.103993","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder marked by dopaminergic (DA) neuron degeneration in the substantia nigra (SN). Conventional dopamine replacement therapies provide limited long-term efficacy and significant side effects. Emerging evidence suggests ferroptosis—a form of cell death driven by iron-dependent lipid peroxidation—contributes to PD pathology, though direct evidence linking dysregulation of ferroptosis-related genes in DA neuron loss in PD remains limited. This study explores the expression of ferroptosis-associated genes in the SN and DA neurons of PD patients, identifying potential therapeutic targets. We analyzed two independent RNA-seq datasets, GSE7621 and GSE8397 (GPL-96), from the GEO database to identify common differentially expressed ferroptosis-related genes in the SN of PD patients. We also conducted Gene Ontology and pathway enrichment analyses of these genes to explore the underlying mechanisms and constructed a protein-protein interaction network. The findings were further validated using an additional dataset, <span><span>GSE49036</span><svg><path></path></svg></span>. We further explored the dysregulation of these ferroptosis-related genes in DA neurons using RNA-seq data <span><span>GSE169755</span><svg><path></path></svg></span>, derived from DA neurons isolated from the SN of PD patients and controls. Lastly, the proposed hypothesis was experimentally validated in an in vitro PD model. This comprehensive multi-dataset analysis uncovers novel insights into the expression of ferroptosis-related genes in PD, suggesting potential biomarkers and therapeutic targets for mitigating DA neuron loss and PD progression.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103993"},"PeriodicalIF":2.6,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific cognitive benefits and anti-inflammatory effects of coumestrol pretreatment in transient global cerebral ischemia","authors":"Cibele Canal Castro ,&nbsp;Adriana Vizuete ,&nbsp;Bruna Ferrary Deniz ,&nbsp;Angela Wyse ,&nbsp;Carlos Alexandre Netto","doi":"10.1016/j.mcn.2025.103991","DOIUrl":"10.1016/j.mcn.2025.103991","url":null,"abstract":"<div><div>Cerebral Global Ischemia (CGI) is a devastating neurological condition affecting millions globally each year, leading to significant inflammatory responses and long-term consequences, including delayed neuronal death and neurocognitive impairment. Following brain injury, resident microglial cells are activated, triggering pro-inflammatory cytokine expression and altering neuroimmune processes in a sex-dependent manner, particularly within the hippocampus. Coumestrol, a plant estrogen, is promoted as an alternative to post-menopausal hormone therapy due to its various mechanisms that enhance brain health, including its anti-inflammatory effects. This study aimed to investigate whether coumestrol pretreatment could attenuate the neuroinflammatory response following CGI by regulating pro-inflammatory pathways (GFAP, S100B, TNF-α, and IL-1β) and reversing CGI-induced memory loss.</div><div>Male and female rats underwent CGI for 10 min or a sham surgery and received an ICV infusion of 20 μg of coumestrol or vehicle 1 h before CGI induction. Our findings revealed intriguing sex-specific effects of coumestrol pretreatment on gliosis following CGI and reperfusion, suggesting modulation of glial responses after ischemic insults. Coumestrol pre-administration significantly reduced levels of pro-inflammatory cytokines TNF-α and IL-1β during both reperfusion periods in both sexes, thereby mitigating CGI-induced neuroinflammation. Moreover, coumestrol pretreatment effectively reduced stroke-induced cognitive impairment, alleviating ischemia-induced memory deficits in both male and female rats. These results demonstrate the coumestrol's ability to attenuate cognitive deficits induced by CGI and highlight its potential sex-specific effects on inflammatory pathways. This study suggests that coumestrol modulates the glial and microglial inflammatory response, offering a promising approach to mitigate memory deficits associated with cerebral global ischemia.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"132 ","pages":"Article 103991"},"PeriodicalIF":2.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}