Experimental Neurology最新文献

{"title":"Remote ischemic conditioning–induced shift from a vulnerable to a tolerant penumbra: A proteomic perspective","authors":"Petra Bonová ,&nbsp;Jana Končeková ,&nbsp;Miroslava Némethová ,&nbsp;Marko Morávek ,&nbsp;Peter Baráth ,&nbsp;Maksym Danchenko ,&nbsp;Martin Bona","doi":"10.1016/j.expneurol.2025.115307","DOIUrl":"10.1016/j.expneurol.2025.115307","url":null,"abstract":"<div><div>The concept of the ischaemic penumbra – stroke tissue with the potential to survive – has opened the door to a wide range of experimental strategies that could benefit the recovery of patients after a stroke. In this study, we used proteomic analysis to examine how remote ischaemic postconditioning (RIPC) mediates a shift from a vulnerable to a tolerant penumbra. We identified 450 differentially abundant proteins between the control group and the groups subjected to ischaemia via middle cerebral artery occlusion with or without RIPC during infarct expansion. The majority of proteins were downregulated following RIPC. Based on Gene Ontology enrichment analysis, we uncovered 24 gene sets significantly influenced during the reprogramming from a vulnerable to a tolerant penumbra. RIPC treatment positively impacted the synthesis of proteins enriched in the cytosol (GO:0005829) but inhibited the abundance of proteins belonging to the cytoskeleton (GO:0005874 microtubule) and the glutamatergic synapse (GO:0098978). The shift to a tolerant phenotype involved overexpression of aminopeptidases (GO:0004177) related to proteolysis (GO:0006508). RIPC also downregulated proteins involved in the tricarboxylic acid cycle (GO:0006099), adenosine triphosphate (ATP) binding (GO:0005524), and ATP hydrolysis (GO:0016887). We validated our proteomic findings by selecting two candidate genes (Map2 and Tubb3) for immunofluorescence. We identified the low-molecular-weight Map2 isoform as a potential marker of the shift from a vulnerable to a tolerant penumbra. In summary, our findings have revealed novel avenues for multimodal investigation of reprogramming the penumbra as part of recovery from stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115307"},"PeriodicalIF":4.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093228","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":"The overexpression of miR-146a in hippocampal microglia via IRAK1/TRAF6/NF-κB pathway improves cognitive function in diabetic mice","authors":"Jingyu Zhang ,&nbsp;Xiaoyun Lin ,&nbsp;Qing Huang ,&nbsp;Zhang Fu ,&nbsp;Yihuan Huang ,&nbsp;Zhiqing Chen ,&nbsp;Ningning Li ,&nbsp;Xiahong Lin","doi":"10.1016/j.expneurol.2025.115291","DOIUrl":"10.1016/j.expneurol.2025.115291","url":null,"abstract":"<div><h3>Background and objective</h3><div>Diabetic encephalopathy (DEP), a central nervous system complication of diabetes, is primarily characterized by cognitive dysfunction. Despite its high prevalence and significant risks, the pathogenesis remains poorly understood. This study investigates the effects and mechanisms of miR-146a on cognitive function in DEP mice.</div></div><div><h3>Methods</h3><div>Type 2 diabetic mice models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. And the Morris water maze test was conducted to assess the learning and memory. The adeno-associated virus was delivered into hippocampus by stereotactic injection to overexpress miR-146a in microglia. The mRNA and protein expression levels were determined by quantitative real-time polymerase chain reaction, immunofluorescence, Western blot, and enzyme-linked immunosorbent assay.</div></div><div><h3>Results</h3><div>DEP mice exhibited significantly reduced miR-146a expression in hippocampal microglia. This reduction was associated with elevated IRAK1, TRAF6, and NF-κB expression, increased markers of pro-inflammatory microglial phenotypes (CD86 and iNOS), and decreased markers of anti-inflammatory phenotypes (Arg-1 and CD206). Pro-inflammatory cytokines TNF-α and IL-6 were elevated, while anti-inflammatory IL-10 was reduced. Eventually, neuronal apoptosis and cognitive dysfunction were evident. Overexpression of miR-146a in hippocampal microglia reversed these molecular and phenotypic abnormalities, decreased neuronal apoptosis, and significantly improved cognitive performance in diabetic mice.</div></div><div><h3>Conclusion</h3><div>Downregulation of miR-146a in hippocampal microglia disrupts immune homeostasis through the IRAK1/TRAF6/NF-κB pathway, contributing to DEP. Targeted overexpression of miR-146a restores immune homeostasis, reduces neuronal apoptosis, and ameliorates cognitive impairment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115291"},"PeriodicalIF":4.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993221","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":"Icariin attenuates oxidative stress via SIRT1/PGC-1α pathway in SAH mice","authors":"Xingwei Lei,&nbsp;Daochen Wen,&nbsp;Zichao Huang,&nbsp;Xiaoguo Li,&nbsp;Liuyang Tang,&nbsp;Yajun Zhu,&nbsp;Zongduo Guo","doi":"10.1016/j.expneurol.2025.115303","DOIUrl":"10.1016/j.expneurol.2025.115303","url":null,"abstract":"<div><div>Oxidative stress plays a pivotal role in the pathological response of subarachnoid hemorrhage (SAH). Icariin (ICA), with its potent antioxidant properties, exerts neuroprotective effects in stroke. This study investigated the beneficial effects of ICA on SAH-induced oxidative damage and its possible molecular mechanisms. The results indicated that ICA treatment improved both short-term and long-term neurobehavioral functions in mice with SAH. ICA significantly inhibited SAH-induced reactive oxygen species (ROS) generation and lipid peroxidation. Simultaneously, ICA restored the activity of the endogenous antioxidant enzyme system. Furthermore, ICA mitigated mitochondrial damage, improved mitochondrial morphology, further reduced neuronal apoptosis, and decreased brain edema following SAH. Mechanistically, ICA suppressed oxidative stress after SAH by activating Sirtuin 1 (SIRT1), subsequently upregulating the expression of PGC-1α. The SIRT1 inhibitor EX527 significantly inhibited ICA-induced SIRT1 activation and abolished the antioxidant and neuroprotective effects of ICA. In cellular experiments, ICA also inhibited ROS production and enhanced cell viability. These effects were associated with SIRT1 activation and were reversed by EX527 treatment. In conclusion, this study explored the protective effects of ICA against SAH-induced oxidative damage, suggesting that ICA could be a potential therapeutic agent for SAH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115303"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931541","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":"Loss of Plxdc2 exacerbates microglia-mediated neuroinflammation and ischemic brain injury","authors":"Lixuan Yang ,&nbsp;Yang Geng ,&nbsp;Yi Qian ,&nbsp;Ningning Zong ,&nbsp;Shengnan Xia ,&nbsp;Haiyan Yang ,&nbsp;Xinyu Bao ,&nbsp;Jian Chen ,&nbsp;Yun Xu","doi":"10.1016/j.expneurol.2025.115302","DOIUrl":"10.1016/j.expneurol.2025.115302","url":null,"abstract":"<div><div>Microglia are the supervisors maintaining intracerebral homeostasis, which function importantly in determining the outcome of ischemic stroke. Plxdc2 is a single-transmembrane protein and mainly studied in the development of central nervous system and cancers, whereas its role in the function of microglia remains elusive. In this study, based on our previous scRNA-seq of ischemic brain and transcriptomic analysis of microglia isolated from the ischemic brain, we found that Plxdc2 was abundantly expressed in microglia and remarkably downregulated after stroke. Further, with adeno-associated virus (AAV) overexpressing or lentivirus interfering Plxdc2 in microglia in vivo, Plxdc2 was proved to protect against ischemic brain injury. Plxdc2 helps maintain microglial homeostatic state both in vitro and in vivo, and downregulation of Plxdc2 exacerbated microglial inflammatory response. In addition, we found that Plxdc2 participated in regulating the activation of NF-κB p65 signaling, and also modulated microglial lipid metabolism. Moreover, Plxdc2 was found to facilitate the activation of PPARγ, which might account for its impact on NF-κB p65 signaling and lipid metabolism in microglia. Overall, our results illustrated a vital role of Plxdc2 in modulating post-stroke microglial activation, which holds potential to be a novel target for immunomodulation in ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115302"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981653","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":"Dynein-regulated brain transduction of AAV.CAP-B10 via cerebral lateral ventricle enhances hippocampal function after traumatic brain injury through Ngf gene delivery in mice","authors":"Jiang-Chang Wang ,&nbsp;Sheng-Hao Ding ,&nbsp;Zheng-Hui He ,&nbsp;Jia-lin Huang ,&nbsp;Wei-Ji Weng ,&nbsp;Ying-Wei Gao ,&nbsp;Ji-Yao Jiang ,&nbsp;Yong Lin ,&nbsp;Jun-Feng Feng","doi":"10.1016/j.expneurol.2025.115285","DOIUrl":"10.1016/j.expneurol.2025.115285","url":null,"abstract":"<div><div>The blood-brain barrier (BBB) poses a significant challenge for the intravenous delivery of drugs targeting central nervous system (CNS) diseases. Recently, a novel adeno-associated virus (AAV)-9 variant, AAV.CAP-B10, has shown promise due to its high BBB-crossing efficiency and low liver toxicity. However, its strain dependency, ability to transduce the brain following cerebral lateral ventricle (CLV) injection, and underlying mechanisms remain unclear. In this study, we intravenously administered AAV.CAP-B10 to C57BL/6 and BALB/c mice to evaluate its ability to cross the BBB. We also injected AAV.CAP-B10 into the CLV of both mouse strains to assess brain transduction and explored its mechanisms using ciliobrevin D, a dynein inhibitor. Additionally, we tested whether AAV.CAP-B10 could deliver the nerve growth factor (<em>Ngf</em>) gene to treat traumatic brain injury (TBI) in mice. Our results showed that intravenous AAV.CAP-B10 effectively crossed the BBB in C57BL/6 mice but not in BALB/c mice. Brain transduction via CLV was significantly reduced in ciliobrevin D-treated mice, implicating dynein in this process. Furthermore, AAV.CAP-B10-mediated <em>Ngf</em> gene expression improved hippocampal function in TBI mice. These findings highlight the strain-dependent BBB penetration of AAV.CAP-B10, its dynein-associated hippocampal transduction via CLV, and its potential as a therapeutic gene vector for TBI treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115285"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937406","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":"Identification of Npas4 as a biomarker for CICI by transcriptomics combined with bioinformatics and machine learning approaches","authors":"Zhenyu He ,&nbsp;Huanhuan Ma ,&nbsp;Yu Zhang ,&nbsp;Liping Chen ,&nbsp;Yueling Pang ,&nbsp;Xiaoshan Ding ,&nbsp;Yanan Wang ,&nbsp;Yongqi Liu ,&nbsp;Ling Li ,&nbsp;Jiawei Li","doi":"10.1016/j.expneurol.2025.115290","DOIUrl":"10.1016/j.expneurol.2025.115290","url":null,"abstract":"<div><div>Chemotherapy is one of the most successful strategies for treating cancer. Unfortunately, up to 70 % of cancer survivors develop cognitive impairment during or after chemotherapy, which severely affects their quality of life. We first established a mouse model of CICI and combined bioinformatics, machine learning, and transcriptome sequencing to screen diagnostic genes associated with CICI. Relevant DEGs were screened by differential analysis, and potential biological functions of DEGs were explored by GO and KEGG analysis. WGCNA analysis was then used to find the most relevant modules for CICI. The diagnostic gene Npas4 was screened by combining the three machine learning methods; its diagnostic value was proved by ROC analysis, GSEA analyzed its potential biological function, and then we preliminarily explored the chemicals associated with Npas4. Our study found that Npas4 can be used as an early diagnostic gene for CICI, which provides a theoretical basis for further research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115290"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004971","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":"The cannabinoid receptor 1 mediates exercise-induced improvements of motor skill learning and performance in parkinsonian mouse","authors":"Talifu Zikereya ,&nbsp;Chuang Liu ,&nbsp;Longwei Wei ,&nbsp;Yinhao Wang ,&nbsp;Zhizhen Zhang ,&nbsp;Chuanliang Han ,&nbsp;Kaixuan Shi ,&nbsp;Wei Chen","doi":"10.1016/j.expneurol.2025.115289","DOIUrl":"10.1016/j.expneurol.2025.115289","url":null,"abstract":"<div><div>The endocannabinoid system (eCBs) modulates corticostriatal circuits through cannabinoid receptor 1 (CB1R). These circuits are crucial for encoding goal-directed and habitual learning behaviors and are implicated in the occurrence and progression of Parkinson's disease (PD). While exercise has been shown to enhance motor performance and reverse learning deficits in PD patients, the underlying molecular mechanisms remain unclear. We hypothesized that a treadmill training program could rescue changes in striatal plasticity and ameliorate early motor and cognitive deficits in mice subjected to an intrastriatal 6-hydroxydopamine injection. Our findings demonstrated that exercise training would improve motor performance and learning abilities in PD mice. Moreover, both immunofluorescence and reverse transcription polymerase chain reaction results suggested that corticostriatal activation decreased CB1R expression in the dorsomedial striatum of PD mice but increased expression in the substantia nigra pars reticulata following treadmill exercise. These results suggest that dysregulated CB1R expression is associated with the pathogenesis of Parkinsonism, highlighting the vital role of the CB1R in corticostriatal pathway functionality enhanced by exercise. Our results suggest the potential benefits of treadmill exercise in alleviating Parkinsonism, providing valuable insights into future potential treating strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115289"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937407","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":"Gene-modified animal models of Parkinson's disease","authors":"Yong Peng ,&nbsp;Dai-yi Jiang ,&nbsp;Shun-yu Yao ,&nbsp;Xiuli Zhang ,&nbsp;Sugimoto Kazuo ,&nbsp;Jia Liu ,&nbsp;Miao-qiao Du ,&nbsp;Lan-xin Lin ,&nbsp;Quan Chen ,&nbsp;Hong Jin","doi":"10.1016/j.expneurol.2025.115287","DOIUrl":"10.1016/j.expneurol.2025.115287","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder that commonly occurs in older individuals and clinically manifests as resting tremors, bradykinesia, muscle stiffness, and impaired postural balance. From a genetic perspective, animal models using gene-editing technologies offer distinct advantages in replicating the pathophysiological traits of PD, while also functionally exploring potential treatment targets. In this review, we highlight the available gene- modified animal models related to various mechanisms of PD, including abnormal expression of alpha-synuclein protein, dysfunction of the autophagy-lysosome system, abnormalities in the ubiquitin-proteasome system, and mitochondrial dysfunction. We further discuss their respective strengths, limitations, and prospects, aiming to provide the most up to date information for the application of PD animal models and the advancement of anti-PD drugs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115287"},"PeriodicalIF":4.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913024","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":"Exosome-based therapies and biomarkers in stroke: Current advances and future directions","authors":"Naresh Poondla ,&nbsp;Ali Babaeizad ,&nbsp;Mohsen Sheykhhasan ,&nbsp;Christopher J. Barry ,&nbsp;Hamed Manoochehri ,&nbsp;Hamid Tanzadehpanah ,&nbsp;Hanie Mahaki ,&nbsp;Sharafaldin Al-Musawi","doi":"10.1016/j.expneurol.2025.115286","DOIUrl":"10.1016/j.expneurol.2025.115286","url":null,"abstract":"<div><div>Stroke is a challenging neurological condition caused by interrupted blood flow to the brain and presents substantial global health concerns due to its prevalence and limited treatment options. Exosomes, tiny vesicles released by cells, are gaining attention for their potential in targeted drug delivery and as diagnostic and therapeutic biomarkers for stroke. This article outlines recent advances in exosome-based drug delivery systems and examines their application in managing stroke.</div><div>Stroke presents with diverse symptoms depending on the brain region affected, and current treatments primarily aim to restore blood flow and manage risk factors. Exosomes exhibit a unique structure and composition and contain bioactive molecules. Their ability to cross the blood-brain barrier and target specific cells makes them promising candidates for precise drug delivery in stroke therapy.</div><div>Exosomes contribute extensively to stroke pathophysiology and present considerable therapeutic promise by promoting neuroprotection and assisting in brain repair mechanisms. They can be engineered to carry various therapeutic substances, such as small molecules, enabling highly specific targeted delivery. Furthermore, the molecular compositions of exosomes reflect the pathological changes observed in stroke, indicating their potential use as biomarkers for early diagnosis, monitoring of disease progression, and creating individualized treatment strategies.</div><div>Despite promising developments, challenges remain in optimizing exosome production, purification, and cargo loading. Further investigations into their biological mechanisms and clinical validation are crucial for translating their potential into tangible benefits for patients. This article highlights recent advances and future prospects in exosome research, underscoring their application as novel diagnostic and therapeutic tools in stroke management.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115286"},"PeriodicalIF":4.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986642","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":"Inhibiting mitochondrial excessive fission alleviates the neuronal damage in Parkinson's disease via regulating PGC-1α mediated mitochondrial biogenesis","authors":"Jingwei Ma ,&nbsp;Yang Yang ,&nbsp;Caixia Zang ,&nbsp;Qiuzhu Chen ,&nbsp;Yueqi Jiang ,&nbsp;Yirong Dong ,&nbsp;Jinrong Wang ,&nbsp;Ning Zhou ,&nbsp;Xing Yang ,&nbsp;Fangfang Li ,&nbsp;Xiuqi Bao ,&nbsp;Dan Zhang","doi":"10.1016/j.expneurol.2025.115288","DOIUrl":"10.1016/j.expneurol.2025.115288","url":null,"abstract":"<div><div>Mitochondrial excessive fission is one of representative pathological features and a principal element triggering the neuronal damage in Parkinson's disease (PD). Inhibiting mitochondrial excessive fission benefits the pathology of PD through promoting mitochondrial biogenesis, but the detailed mechanism has not been clarified. In our study, we revealed that inhibiting mitochondrial excessive fission by Mdivi-1, the dynamin related protein 1 (DRP1) inhibitor, increased the expression and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), as well as its downstream transcriptional factors, nuclear respiratory factor 1/2 (NRF1/2) and mitochondrial transcription factor A (TFAM), and therefore promoted mitochondrial biogenesis. Suppression of mitochondrial excessive fission alleviated dopaminergic synaptic injury, neuronal apoptosis and motor dysfunction, while inhibiting PGC-1α attenuated these ameliorative effects in both <em>in-vitro</em> and <em>in-vivo</em> PD models. Mechanistic study showed that inhibiting mitochondrial excessive fission facilitated the expression of PGC-1α, NRF1 and TFAM by activation of Ca²⁺/calmodulin-dependent serine/threonine kinase II (CaMKII)/cAMP-response element binding protein (CREB) pathway. Inhibiting mitochondrial excessive fission also activated AMP-activated serine/threonine kinase (AMPK)/Sirtuin1 (Sirt1) pathway, and then phosphorylated and deacetylated PGC-1α by post-translational modifications. In conclusion, inhibiting mitochondrial excessive fission could promote mitochondrial biogenesis through activation of PGC-1α and therefore rescue the impaired dopaminergic neurons, which provided evidence for targeting mitochondrial excessive fission for the treatment of PD and new drug developments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115288"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948857","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}