Cellular and Molecular Neurobiology最新文献

{"title":"The Role of Estrogen in Mitochondrial Disease.","authors":"Xi Huang, Cun-Hui Pan, Fei Yin, Jing Peng, Li Yang","doi":"10.1007/s10571-025-01592-8","DOIUrl":"10.1007/s10571-025-01592-8","url":null,"abstract":"<p><p>This review aims to investigate the potential role of estrogen in various mitochondrial diseases, such as Leber's Hereditary Optic Neuropathy and Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes, focusing on its effects on aging, oxidative stress, mitochondrial biogenesis, and mitophagy. Mitochondrial diseases have become important in modern medical research due to their complex genetic background and diverse clinical manifestations. Studies in recent years have shown that estrogen plays an essential role in physiological regulation and may also affect the health status of cells by regulating mitochondrial function, which in turn affects the occurrence and development of diseases. However, there is still a lack of systematic review of estrogen's specific mechanisms and roles in these diseases. This review will synthesize the relevant literature to explore the association between estrogen and mitochondrial diseases and its possible therapeutic prospects, aiming to provide a theoretical basis and reference for future research.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"68"},"PeriodicalIF":3.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of P2Y6 Receptor-Mediated Microglia Phagocytosis Aggravates Brain Injury in Mice of Intracerebral Hemorrhage.","authors":"Ying Xu, Weiya Li, Jing Zhang, Weiwei Gao, Ting Zhang, Qing Chen, Nan Wang, Yongjia Zhou, Fengjiao Zhang, Jiahao Qin","doi":"10.1007/s10571-025-01573-x","DOIUrl":"10.1007/s10571-025-01573-x","url":null,"abstract":"<p><p>Intracerebral hemorrhage (ICH) is a devastating stroke subtype leading to severe sensorimotor dysfunction. Many studies showed that microglia phagocytosis could promote hematoma absorption, and scavenger receptors expressed on microglia were associated with its phagocytosis. As a specific phagocytic receptor, blocking the P2Y6 receptor (P2Y6R) with MRS2578 (3 mg/kg) could inhibit the phagocytic activity of microglia, which had been reported in a variety of neurological disorders, such as cerebral ischemia, Parkinson's diseases and neurodegenerative diseases. But the effects of P2Y6R-mediated microglia phagocytosis on the prognosis of ICH are still lacking. In the present study, we showed that P2Y6R expression elevated and peaked at day 3 after ICH. And treatment with MRS2578 (3 mg/kg) for three consecutive days could impair the phagocytosis of microglia, accompanied by delayed hematoma absorption rate, aggravated brain edema and blood-brain barrier disruption, as well as impaired neurological deficit in ICH mice. MRS2578 treatment also increased the expression of pro-inflammatory factors (TNF-α, iNOS) after ICH. Furthermore, MRS2578 treatment further increased the expression of NF-κB, which regulates the expression of these pro-inflammatory cytokines. In summary, our results suggested that regulating microglial phagocytosis could improve the prognosis of ICH, and P2Y6R offered a meaningful target.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"67"},"PeriodicalIF":3.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-124 and MiR-155 as Therapeutic Targets in Microglia-Mediated Inflammation in Multiple Sclerosis.","authors":"Elmira Roshani Asl, Seyedeh Elnaz Hosseini, Fatemeh Tahmasebi, Nadia Bolandi, Shirin Barati","doi":"10.1007/s10571-025-01578-6","DOIUrl":"10.1007/s10571-025-01578-6","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic inflammatory disease associated with demyelination and microglial activation. Significant progress has recently been made in the development of strategies to treat MS with a focus on microglial cells. In response to injury, microglia, a population of mononuclear phagocytic cells, change from quiescent to activated. M1 microglia produce pro-inflammatory cytokines that cause additional injury, thus they are considered neurotoxic microglia. M2 microglia release anti-inflammatory factors that lead to the suppression of inflammatory responses; therefore, they have a neurotrophic phenotype. The balance between M1 and M2 phenotypes is important for nerve recovery. In neurodegenerative diseases, activated microglia are excessively shifted toward M1 or neurotoxic phenotype due to microRNA (miRNA) dysregulation. The miRNA as a class of non-coding RNAs, control the neuroinflammatory process by activation of microglia. The miR-124 is partly responsible for suppressing the neuroprotective and inflammatory processes by preventing microglia activation. Meanwhile, the microRNA 155, which is induced by pro-inflammatory agents in microglia, promotes the inflammatory process. Several studies have shown that in MS pathogenesis, miR-124 as an anti-inflammatory marker is significantly downregulated, while miR-155 shows an increase. In this study, we will investigate the role of miR-124 and miR-155 in the activation and alteration of microglial phenotype. Finding the relationship between microRNAs and glial cells and inflammation in MS may be used as a therapeutic method to reduce the symptoms in MS patients.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"63"},"PeriodicalIF":4.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Consequences of a Missense PHF21A Variant, c.1285G > A, Associated With Syndromic Neurodevelopmental Disorder.","authors":"Cecilia M Gavilan, Yumie Murata-Nakamura, Robert Porter, Bradley Cutler, Sehj Rai, Hyung-Goo Kim, Shigeki Iwase","doi":"10.1007/s10571-025-01584-8","DOIUrl":"10.1007/s10571-025-01584-8","url":null,"abstract":"<p><p>PHF21A is a histone reader protein that recognizes unmethylated H3 lysine 4 and binds to DNA through its AT-hook motif. PHF21A heterozygosity is associated with intellectual disability, behavioral issues, and craniofacial dysmorphism, with or without seizures (IDDBCS), also known as PHF21A-related neurodevelopmental disorders. To date, the only missense variant associated with PHF21A-related disorders is c.1285G > A, which substitutes one of the core amino acids consisting of the AT-hook motif. This variant, located at the last nucleotide of exon 13, potentially disrupts both alternative splicing and the DNA binding function, providing a unique opportunity to investigate the molecular mechanisms underlying the disorders. Here, we systematically investigated the consequences of this variant on mRNA splicing and DNA binding. Our results indicate that the variant significantly reduced the splicing efficiency of PHF21A isoforms while maintaining DNA binding capability. Thus, reduced dosage rather than impaired DNA binding likely contributes to the cognitive impairments seen in the individual with this variant.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"62"},"PeriodicalIF":4.8,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal Effects of the Plasma Proteome on Vascular Dementia Risk: A Mendelian Randomization Study with Experimental Validation.","authors":"Yunmeng Chen, Chunyan Guo, Xiao Liang, Xiansu Chi, Zixuan Zhang, Ze Chang, Yunling Zhang","doi":"10.1007/s10571-025-01583-9","DOIUrl":"10.1007/s10571-025-01583-9","url":null,"abstract":"<p><p>Vascular dementia (VaD) is a prevalent form of dementia caused by cerebrovascular disease, leading to cognitive impairment. While various risk factors have been identified, the role of plasma proteins in VaD etiology remains poorly understood. This study employs Mendelian randomization (MR) to investigate the causal relationship between plasma proteins and VaD risk, complemented by experimental validation. We conducted a two-sample MR analysis using summary statistics from genome-wide association studies (GWAS) on plasma proteins and VaD. Plasma protein data were derived from the deCODE Health study, encompassing 35,559 Icelandic participants and genetic associations for 4907 circulating proteins. VaD GWAS data were obtained from the FinnGen biobank, comprising 2717 VaD patients and 393,024 controls. Instrumental variables (IVs) were selected based on genome-wide significance thresholds (P < 5 × 10^-8 for plasma proteins, P < 5 × 10^-6 for VaD). The primary analysis used inverse variance weighting (IVW), supplemented by weighted median, MR-Egger, simple mode, and weighted mode methods. The Sensitivity analyses included heterogeneity tests, horizontal pleiotropy assessments, and leave-one-out analyses. Additionally, a 2-vessel occlusion (2-VO) animal model was used to validate key genes, with gene expression measured by quantitative real-time PCR (qPCR). Our initial MR analysis identified 123 plasma proteins significantly associated with VaD (P < 0.05), of which 12 maintained significance after FDR correction (FDR < 0.05). Importantly, the comprehensive pleiotropy analysis ultimately confirmed robust causal relationships for nine of these proteins with VaD. Among these, MED4 (OR = 1.819, 95% CI: 1.493-2.217, FDR < 0.001), COPS7B (OR = 1.136, 95% CI: 1.076-1.199, FDR < 0.001), CSF3 (OR = 1.262, 95% CI: 1.139-1.398, FDR < 0.001), IL26 (OR = 1.125, 95% CI: 1.066-1.186, FDR < 0.001), NRXN1 (OR = 1.125, 95% CI: 1.066-1.187, FDR < 0.001), LRRTM4 (OR = 1.418, 95% CI: 1.225-1.614, FDR < 0.001), and MAGEA3 (OR = 1.883, 95% CI: 1.403-2.529, FDR < 0.001) were identified as risk factors for VaD, with MED4 showing the strongest association. Conversely, CRYZL1 (OR = 0.387, 95% CI: 0.246-0.609, FDR < 0.001) and TMCC3 (OR = 0.327, 95% CI: 0.191-0.558, FDR < 0.001) were identified as protective factors. The Reverse MR analysis indicated no significant association between VaD and the 9 plasma proteins. In the 2-VO model, MED4 expression was significantly reduced, while NRXN1 expression was elevated compared to the sham group (P < 0.05). This study identifies several plasma proteins with a significant causal relationship with VaD, highlighting MED4 and NRXN1 as potential biomarkers and therapeutic targets. The findings were further validated in an experimental model, providing robust evidence for their roles in VaD pathogenesis. Further research is needed to elucidate the underlying mechanisms and confirm their clinical relevance.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"66"},"PeriodicalIF":3.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Plasma m6A Demethylase FTO Levels Predict Favorable Outcomes Following Acute Ischemic Stroke.","authors":"Junfen Fan, Liyuan Zhong, Tong Shen, Yilin Wang, Ziping Han, Haiping Zhao, Feng Yan, Rongliang Wang, Yangmin Zheng, Zhen Tao, Yumin Luo, Ping Liu","doi":"10.1007/s10571-025-01591-9","DOIUrl":"10.1007/s10571-025-01591-9","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) modification is prevalent in the mammalian brain and functions as a significant epigenetic regulator in neurological disorders, including ischemic stroke. The fat mass and obesity-associated protein (FTO) was the first m6A demethylase to be identified. The objective of this study was to assess the prognostic significance of FTO in patients with acute ischemic stroke (AIS). A cohort consisting of 201 AIS patients and 53 healthy controls were enrolled, and their plasma FTO concentrations were measured. The findings demonstrated that FTO levels were remarkably lower in AIS patients compared to healthy controls (254.80 [229.89, 274.77] vs. 395.67 [271.34, 544.17], p < 0.001), and they were significantly diminished in patients with unfavorable outcomes compared to those with favorable outcomes (250.73 [208.34, 290.77] vs. 257.03 [236.47, 283.96], p = 0.016). Additionally, FTO concentration exhibited a negative correlation with 3-month modified Rankin scale (mRS) scores in ischemic stroke patients (r = - 0.1635, p = 0.0204). Univariate and multivariate logistic regression analyses revealed that plasma FTO levels were associated with the functional outcomes at 3 months. After adjusting for potential confounding variables, elevated FTO levels independently predicted the 3-month favorable outcomes (odds ratio [OR] = 0.986 (0.977-0.996), p = 0.004). Besides, the inclusion of FTO in the clinical model notably enhanced the discrimination and risk reclassification (integrated discrimination improvement = 5.34% (2.37-8.31%), p = 0.0004); continuous net reclassification improvement = 44.07% (17.33-70.82%), p = 0.0012). A nomogram incorporating FTO showed good calibration, discrimination, and clinical utility. Consequently, our study demonstrated that admission plasma FTO levels are independently linked to the 3-month outcomes for patients with AIS.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"64"},"PeriodicalIF":3.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Perivascular Macrophages in Alzheimer's Disease: Insights from Single-Cell Sequencing and Mendelian Randomization.","authors":"Min Zhang, Shufang Liu, Yanan Zhao, Ping Wu, Shouyuan Tian, Zhifang Wu, Sijin Li","doi":"10.1007/s10571-025-01590-w","DOIUrl":"10.1007/s10571-025-01590-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a leading cause of dementia characterized by neuroinflammation and immune dysregulation. Perivascular macrophages (PVMs) play a crucial role in the onset and progression of AD, yet the specific molecular mechanisms remain understudied. This study explored the molecular mechanisms of PVMs in AD using single-cell sequencing combined with Mendelian randomization (MR) analysis. We analyzed data from GSE264648 and eQTLGen and identified four key genes that were significantly associated with AD risk: IFNGR1, KLHL5, NUMB, and WDFY4. Functional annotation revealed that PVMs were involved in immune regulation and metabolic pathways, particularly IL-6_JAK_STAT3 and Notch signaling. Immune infiltration analysis showed increased M2 macrophages in AD patients, suggesting their roles in neuroinflammation. Pseudo-time analysis highlighted developmental shifts in PVMs during disease progression. Our findings offer novel insights into the role of PVMs in AD and provide a foundation for future research on modulating neuroinflammation and slowing AD progression through PVM-targeted interventions.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"65"},"PeriodicalIF":3.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Druggable Targets for Postpartum Depression: A Mendelian Randomization and Colocalization Study.","authors":"Song Wu, Meihong Shen, Huiyan Wang, Wenbo Zhou","doi":"10.1007/s10571-025-01581-x","DOIUrl":"10.1007/s10571-025-01581-x","url":null,"abstract":"<p><p>Postpartum depression (PPD) remains a complex disorder with poorly understood genetic underpinnings. This study systematically evaluated the genetic susceptibility of PPD and identified potential therapeutic targets using Mendelian Randomization (MR) approach. Using a two-sample MR approach, the study assessed the causal effects of expression quantitative trait loci (eQTLs) of druggable genes in blood on PPD, which was sourced from the FinnGen. The primary analytical method was the inverse variance weighted, supplemented by a series sensitivity analyses. Summary-data-based Mendelian Randomization (SMR) analysis was used to validate the identified genes, and Bayesian colocalization analysis evaluated shared causal variants and colocalization probabilities between significant targets and PPD. A Phenome-Wide Association Study (PheWAS) was conducted to assess the associations of established PPD markers with other traits to exclude potential side effects. The results showed that the eQTLs of 12 druggable genes were significantly associated with PPD susceptibility. Seven genes were identified as risk factors, and the expression levels of five genes significantly reduced PPD susceptibility. Colocalization analysis supported the hypothesis that PPD may be associated with shared causal variants of ALDH16A1 (OR = 1.09, 95% CI 1.05-1.13, PP.H4 = 0.78) and SLC29A4 (OR = 1.36, 95% CI 1.23-1.50, PP.H4 = 0.76). The PheWAS did not indicate potential side effects for these two therapeutic targets. This study identified new genetic susceptibilities and potential therapeutic targets associated with PPD, providing novel insights for clinical diagnosis and treatment, and offering new research directions for understanding the molecular mechanisms of PPD.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"61"},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Emotional Stress and Adaptive Behavior with Stroke Risk: A Mendelian Randomization Study.","authors":"Jianyu Liu, Chunlan Pu, Cao Liu, Qiang Zhou, Da Liu, Tianqi Lu, Zhouyang Liu, Xing Guo, Hua Liu","doi":"10.1007/s10571-025-01577-7","DOIUrl":"10.1007/s10571-025-01577-7","url":null,"abstract":"<p><p>Although emotional stress and adaptive behavior are known to influence cardiovascular health, direct evidence linking them to stroke remains limited. This study aims to clarify the associations between emotional stress, adaptive behaviors, and the risk of stroke. We conducted a two-sample Mendelian randomization analysis using data from the UK Biobank, the European Bioinformatics Institute, the Integrative Epidemiology Unit, and the FinnGen project. Indirect effects were estimated using the product of coefficients method. Low satisfaction with family relationships was associated with increased risks of all stroke and ischemic stroke. Mood swings were linked to higher risks of all stroke, ischemic stroke, and large-artery stroke, while feelings of tension were associated with large-artery stroke and small vessel stroke. Interestingly, nervousness was inversely associated with intracerebral hemorrhage risk. Participation in group leisure activities was associated with reduced risks of all stroke, ischemic stroke, and small vessel stroke. In contrast, several adaptive behaviors were linked to increased stroke risk, including vigorous physical activity (all stroke), summer outdoor activities (all stroke and ischemic stroke), winter outdoor activities (all stroke), and prolonged television watching (all stroke, ischemic stroke, and large-artery stroke). Mediation analyses suggested that hypertension, type 2 diabetes, atherosclerotic heart disease, and chronic ischemic heart disease may partially mediate these associations. The study provides genetic evidence supporting a potential causal relationship between emotional stress, adaptive behaviors, and stroke subtypes. Individuals can easily modify adaptive behaviors and manage emotional stress in their daily routines. Understanding these associations may inform future strategies for stroke prevention; however, due to limitations inherent in the current study design, our findings require further validation in large-scale prospective cohort studies.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"59"},"PeriodicalIF":3.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senolytic Treatment Attenuates Global Ischemic Brain Injury and Enhances Cognitive Recovery by Targeting Mitochondria.","authors":"Caihong Gu, Ting Guo, Xiaobing Chen, Xinyu Zhou, Yong Sun","doi":"10.1007/s10571-025-01580-y","DOIUrl":"10.1007/s10571-025-01580-y","url":null,"abstract":"<p><p>The benefits of senolytic therapy have been known in a series of age-related diseases, whereas its potential roles in global cerebral ischemic (GCI) brain injury remain unexplored. In current study, we aim to investigate the effects of combined senolytics Dasatinib plus Quercetin (D&Q) treatment in GCI and the underlying mechanisms in a mouse model. We firstly report that 12-week post-GCI D&Q treatment effectively eliminated cellular senescence of astrocytes and microglia in the hippocampus of mice brain, followed by decreased release of the potent inflammatory senescence-associated secretory phenotypes (SASP). Further mechanistic analysis suggested that D&Q administration can effectively regulate mitochondrial function as a critical downstream target. D&Q treatment inhibited GCI-induced mitochondrial fragmentation and maintained mitochondrial integrity. Subsequently, D&Q treatment improved the mitochondrial metabolic function by enhancing mitochondrial cytochrome c oxidase (CCO) activity and ATP production. Moreover, D&Q treatment reversed the decline of mitochondrial antioxidant enzyme SOD2 and reduced the ROS accumulation and suppressed oxidative damage to cellular protein structure. Further investigation indicated D&Q treatment protected the hippocampal neurons after GCI by mitigating the dendritic injury and neuronal apoptotic signaling. Extensive behavioral tests assessed the functional outcomes and showed that D&Q treatment effectively preserved hippocampus-dependent spatial reference memory and recognition memory, and mitigated GCI-induced anxiety and depression levels. Taken together, our study provides leading evidence for the neuroprotective roles of the senolytics D&Q in GCI model and identifies regulation of mitochondrial functions could be the key underlying mechanism. These findings offer novel insights into the potential clinical applications of senolytic agents in therapy.</p>","PeriodicalId":9742,"journal":{"name":"Cellular and Molecular Neurobiology","volume":"45 1","pages":"60"},"PeriodicalIF":3.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}