Experimental Neurology最新文献

{"title":"Corrigendum to “TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway” [Experimental Neurology volume 382 (2024) 114975]","authors":"Jundong Kong , Qiangqiang Zhang , Haohong Zheng , Diandong Tang , Li Fang , Shuaihao An , Jian Li , Zhongkai Fan","doi":"10.1016/j.expneurol.2024.114998","DOIUrl":"10.1016/j.expneurol.2024.114998","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 114998"},"PeriodicalIF":4.6,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461509","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":"Cold atmospheric plasma-activated saline alleviates secondary injury post-SCI by inhibiting extracellular matrix remodeling and infiltration of proinflammatory macrophages","authors":"Yan Jiang ,&nbsp;Li-Yun Wang ,&nbsp;Yi Liu ,&nbsp;Jian-Jian Li ,&nbsp;Sheng-Quan Zhang ,&nbsp;Xiao-Jun Feng ,&nbsp;Chun-Jun Yang ,&nbsp;Yun Zhou","doi":"10.1016/j.expneurol.2024.115004","DOIUrl":"10.1016/j.expneurol.2024.115004","url":null,"abstract":"<div><h3>Background</h3><div>Cold atmospheric plasma (CAP) has been shown to improve the recovery of transected peripheral nerves. We determined the protective role of CAP-activated saline (CAP-AS) treatment in the acute and subacute stages of spinal cord injury (SCI) in mice.</div></div><div><h3>Methods</h3><div>C57BL/6 SCI mice were treated with CAP-AS for 14 days. Injury recovery was assessed weekly for four weeks by conducting motor function tests, including the Basso Mouse Scale (BMS) and footprint test. Transcriptome analysis was conducted on day 14 to elucidate potential mechanisms, which were further validated through immunofluorescence examinations of the injured spinal cord tissues on day 28 and the levels of proinflammatory cytokines produced by macrophages in vitro.</div></div><div><h3>Results</h3><div>Compared to the SCI group, the CAP-AS-treated groups presented significantly better hindlimb motor function after four weeks. The downregulated (SCI vs. SCI + CAP-AS, with CAP-AS activated for 20 min) differentially expressed genes (DEGs) were enriched in the extracellular region, extracellular matrix (ECM), and ECM-receptor interaction. In contrast, the upregulated DEGs were enriched in immune response-associated pathways. Histological changes in the CAP-AS-treated groups were observed to further validate the predicted mechanisms 28 days post-injury. The alleviation of secondary injury was confirmed by an increase in GFAP-positive and NFH-positive areas, and enhanced outgrowth of 5-HT-positive fibers. Inhibited ECM remodeling was confirmed by a decrease in the areas positive for PDGFRβ, fibronectin, and laminin. A decrease in the infiltration of macrophages and activation of microglia was determined by a decrease in CD68-positive and F4/80-positive areas. The inhibitory effect of CAP-AS on inflammation was further supported by a decrease in the levels of the proinflammatory cytokines IL-1β, IL-6, and TNF-α in CAP-AS-treated M1 macrophages.</div></div><div><h3>Conclusion</h3><div>CAP-AS can alleviate secondary injury in SCI model mice by inhibiting ECM remodeling in injured tissues and reducing the infiltration or activation of proinflammatory macrophages/microglia.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115004"},"PeriodicalIF":4.6,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461508","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":"Optineurin regulates motor and learning behaviors by affecting dopaminergic neuron survival in mice","authors":"Xianfei Yang ,&nbsp;Ruoling Zheng ,&nbsp;Hongyao Zhang ,&nbsp;Zixian Ou ,&nbsp;Sha Wan ,&nbsp;Dongfeng Lin ,&nbsp;Jianguo Yan ,&nbsp;Mingyue Jin ,&nbsp;Jie Tan","doi":"10.1016/j.expneurol.2024.115007","DOIUrl":"10.1016/j.expneurol.2024.115007","url":null,"abstract":"<div><div>Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115007"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461512","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":"SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice","authors":"Qiuhong Jiang ,&nbsp;Ge Li ,&nbsp;Huacheng Wang ,&nbsp;Weineng Chen ,&nbsp;Fengyin Liang ,&nbsp;Haifan Kong ,&nbsp;Tara S.R. Chen ,&nbsp;Lishan Lin ,&nbsp;Hua Hong ,&nbsp;Zhong Pei","doi":"10.1016/j.expneurol.2024.115020","DOIUrl":"10.1016/j.expneurol.2024.115020","url":null,"abstract":"<div><div>Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment. However, their roles remain unknown in COVID-19 with cognitive impairment. We stimulated BV2 cells with S1 protein <em>in vitro</em> and injected the hippocampi of wild-type (WT) mice, NLRP3 knockout (KO), and microglia NLRP3 KO mice <em>in vivo</em> with S1 protein to induce cognitive impairment. We assessed exploratory behavior as associative memory using novel object recognition and Morris water maze tests. Neuroinflammation was analyzed using immunofluorescence and western blotting to detect inflammatory markers. Co-localized NLRP3 and S1 proteins were investigated using confocal microscopy. We found that S1 protein injection led to cognitive impairment, neuronal loss, and neuroinflammation by activating NLRP3 inflammation, and this was reduced by global NLRP3 KO and microglia NLRP3 KO. Furthermore, TAK 242, a specific inhibitor of Toll-like receptor-4, resulted in a significant reduction in NLRP3 and pro-IL-1β in BV2 cells with S1 protein stimulation. These results reveal a distinct mechanism through which the SARS-CoV-2 spike S1 protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115020"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461516","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":"Nucleophosmin 1 overexpression enhances neuroprotection by attenuating cellular stress in traumatic brain injury","authors":"Jiashuo Zhao ,&nbsp;Weixin Xing ,&nbsp;Chengyuan Ji ,&nbsp;Hongwei Hu ,&nbsp;Yuanqing Zhang ,&nbsp;Zongqi Wang ,&nbsp;Jiangang Liu","doi":"10.1016/j.expneurol.2024.115019","DOIUrl":"10.1016/j.expneurol.2024.115019","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic Brain Injury (TBI) is a multifaceted injury that can cause a wide range of symptoms and impairments, leading to significant effects on brain function. Nucleophosmin 1 (NPM1), a versatile phosphoprotein located in the nucleolus, is being recognized as a possible controller of cellular stress reactions and could be important in reducing neuro dysfunction caused by TBI. However the critical roles of NPM1 in cellular stress in TBI remains unclear.</div></div><div><h3>Methods</h3><div>We employed a control cortical impact mouse model and a scratch-induced primary neuronal culture model. Hematoxylin and eosin staining was used to evaluate tissue damage and cellular changes, with NPM1 expression in the cortical area assessed through immunofluorescence staining and Western blot analysis. Neuronal morphology was assessed using Nissl staining. Behavioral assessments were performed to evaluate the impact of NPM1 overexpression on neurobehavioral results in TBI mice. Mitochondrial function was assessed using an Extracellular Flux Analyzer.</div></div><div><h3>Results</h3><div>Following TBI, an increase in NPM1 expression was observed, with a peak at 72 h post-injury. Increased levels of NPM1 resulted in decreased neuronal cell death, as shown by Nissl staining, and lower levels of Caspase 8, APE1, H2AX, and 8-OHDG expression, indicating a reduction in DNA damage. NPM1 overexpression also resulted in improved neurobehavioral outcomes, characterized by decreased neurological deficits and enhanced motor function post-TBI. Additionally, <em>in vitro</em>, scratch-induction experiments revealed that NPM1 overexpression mitigated mitochondrial damage, as evidenced by the downregulation of P53, BCL2, and Cyto C expression levels and improvements in mitochondrial respiratory function.</div></div><div><h3>Conclusion</h3><div>These findings suggest NPM1 as a promising target for developing interventions to alleviate TBI-related cellular stress and promote neuronal survival.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115019"},"PeriodicalIF":4.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461511","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":"Time-dependent arachidonic acid metabolism and functional changes in rats bladder tissue after suprasacral spinal cord injury","authors":"Yi Rong ,&nbsp;Yinbo Kang ,&nbsp;Jie Wen ,&nbsp;Qian Gong ,&nbsp;Wenlong Zhang ,&nbsp;Ke Sun ,&nbsp;Weibing Shuang","doi":"10.1016/j.expneurol.2024.114989","DOIUrl":"10.1016/j.expneurol.2024.114989","url":null,"abstract":"<div><h3>Background</h3><div>A critical aspect affecting the quality of life in Traumatic spinal cord injury (TSCI) patients is bladder dysfunction. Metabolities in arachidonic acid are crucial lipid signaling molecules involved innumerous physiological processes. In this study, We are the first use eicosanoid metabolomics detrusor contraction examine, to assess the effect of the arachidonic acid metabolic in bladder dysfunction following TSCI. In additon, we explore the time of inflammatory and function changes in bladder tissue.</div></div><div><h3>Methods</h3><div>Adult male Sprague-Dawley rats were subjected to improved Weight Drop method surgeries. Detrusor contraction examination, urodynamic examination, eicosanoid metabolomics, transmission electron microscopy, Elisa and histological staining were performed to assess the change of inflammatory, metabolic and function variation over time after TSCI.</div></div><div><h3>Results</h3><div>Following TSCI, before the variations of bladder function, inflammatory changes including the increase of inflammatory factors, mitochondrial damage, and slight lipid peroxidation, occurred in bladder tissue. And the inflammatory changes gradually decreases over time. However, From the third day after TSCI, secondary lesions appeared in bladder tissue. Not only did inflammation-related indexes increase again, the degree of mitochondrial damage and lipid peroxidation increased, but also the contractility of detrusor began to change significantly. We also found that the content of metabolites in arachidonic acid metabolic pathway and the degree of detrusor contractility change showed a strong correlation. In addition, we found that rats had moved beyond the spinal shock stage on the seventh day after TSCI.</div></div><div><h3>Conclusion</h3><div>Altogether, we are the first to demonstrate that abnormal arachidonic acid metabolism plays an important role in bladder dysfunction after TSCI. We also demonstrate that 3d is a critical juncture for changes in rat bladder tissue, which indicates it is an important juncture in the treatment of neurogenic bladder.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 114989"},"PeriodicalIF":4.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461524","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":"GlyT1 inhibition promotes neuroprotection in the middle cerebral artery occlusion model through the activation of GluN2A-containing NMDAR","authors":"Daniel Pereira Cavalcante ,&nbsp;Antonio Ítalo dos Santos Nunes ,&nbsp;Eduardo Rosa da Silva ,&nbsp;Gustavo Almeida de Carvalho ,&nbsp;Raphaela Almeida Chiareli ,&nbsp;Onésia Cristina Oliveira-Lima ,&nbsp;Giovanni Ortiz-Leoncini ,&nbsp;Henning Ulrich ,&nbsp;Renato Santiago Gomez ,&nbsp;Mauro Cunha Xavier Pinto","doi":"10.1016/j.expneurol.2024.115006","DOIUrl":"10.1016/j.expneurol.2024.115006","url":null,"abstract":"<div><div>Glycine Transporter Type 1 (GlyT1) inhibition confers neuroprotection against different forms of cerebral damage. This effect occurs through the elevation of synaptic glycine concentrations, which enhances <em>N</em>-methyl-<span>d</span>-aspartate receptor (NMDAR) activation by glutamate. To investigate the neuroprotective mechanism of GlyT1 inhibition, we used the Middle Cerebral Artery Occlusion (MCAO) model in male C57BL/6 mice, aged 10–12 weeks. We administered N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl] sarcosine (NFPS), a GlyT1 inhibitor, 24 h prior to ischemia induction. NFPS pretreatment provided significant neuroprotection in the MCAO model, associated with modulation of pathways related to long-term potentiation. Specifically, GluN2A subunit expression was upregulated, while GluN2B subunit expression was downregulated in cortical areas, correlating with enhanced phosphorylation of CaMKIV and CREB proteins. Coadministration with the GluN2B antagonist Eliprodil or the CREB inhibitor C646 did not affect the neuroprotective effects of NFPS pretreatment, but TCN-201, a specific GluN2A antagonist, disrupted these effects. These findings suggest that GlyT1 inhibition mediates neuroprotection through activation of GluN2A-containing NMDARs and the GluN2A/CaMKIV/CREB signaling cascade, thereby modulating the balance between GluN2A and GluN2B subunits.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115006"},"PeriodicalIF":4.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461522","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":"Early intervention using long-term rhythmic pulsed magnetic stimulation alleviates cognitive decline in a 5xFAD mouse model of Alzheimer's disease","authors":"Xue Wang ,&nbsp;Qingmeng Wang ,&nbsp;Xuting Wang ,&nbsp;Haoyu Zhao ,&nbsp;Chuncheng Zhao ,&nbsp;Yangkun Jiao ,&nbsp;Hongkai Shi ,&nbsp;Changyou Chen ,&nbsp;Haitao Chen ,&nbsp;Pingping Wang ,&nbsp;Tao Song","doi":"10.1016/j.expneurol.2024.115002","DOIUrl":"10.1016/j.expneurol.2024.115002","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is the most prevalent form of dementia, but no effective therapeutic strategy is available to date. Rhythmic magnetic stimulation is an attractive means of neuron modulation that could be beneficial for restoring learning and memory abilities.</div></div><div><h3>Objective</h3><div>To assess the effect of a compound pulsed rhythmic magnetic field (cPMF) on cognition during AD progression and to explore the appropriate cPMF intervention period.</div></div><div><h3>Methods</h3><div>Female 5xFAD mice aged 10 weeks and 18 weeks were exposed to cPMF with a carrier frequency of 40 Hz, repeated at 5 Hz for 1 h/d for 8 consecutive weeks. The Morris water maze (MWM) test was used for cognitive behavioral assessment. Furthermore, changes in molecular pathology within the brain were detected using immunofluorescence staining and real-time PCR.</div></div><div><h3>Results</h3><div>10-week-old AD mice treated with cPMF explored the target quadrant more frequently than sham-exposed AD mice in MWM test, exhibiting improved learning and memory abilities. Additionally, cPMF exposure alleviated Aβ plaque deposition and astrogliosis in the AD brain. Moreover, neurotrophic factor fibroblast growth factor 1 (FGF1) in the AD brain was upregulated by cPMF treatment. However, in 18-week-old AD mice treated with cPMF, cognitive performance and <em>Fgf1</em> gene expression were not significantly improved, although Aβ plaque deposition and astrogliosis were alleviated.</div></div><div><h3>Conclusion</h3><div>Early intervention via long-term rhythmic cPMF stimulation may alleviate the histopathological features and enhance neuroprotective gene <em>Fgf1</em> expression, thereby improving the cognitive performance of 5xFAD mice, which should provide promising insight for the clinical treatment of patients with AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115002"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461521","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":"Progress in the regulatory mechanism of mitophagy in chronic cerebral ischemic neuronal injury","authors":"Lihong Li ,&nbsp;Rui Yuan ,&nbsp;Moxin Wu ,&nbsp;Xiaoping Yin ,&nbsp;Manqing Zhang ,&nbsp;Zhiying Chen","doi":"10.1016/j.expneurol.2024.115003","DOIUrl":"10.1016/j.expneurol.2024.115003","url":null,"abstract":"<div><div>Chronic cerebral ischemia (CCI) is a common clinical syndrome that can impact various cerebrovascular diseases. Its pathological mechanism of injury involves energy imbalance, oxidative stress, inflammatory response, and many other processes. Neuronal damage occurs in a complex and multifaceted manner. This article provides a detailed discussion of the activation and inhibition mechanisms of mitophagy under cerebral ischemia and considers the advantages and disadvantages of mitophagy in the recovery process of ischemic brain injury. Finally, we address the future direction of research on neuronal injury and the regulatory mechanisms of mitophagy in chronic cerebral ischemia. Future studies should focus on drug intervention at specific regulatory points and the cross-regulation of related signaling pathways to comprehensively deepen understanding of the mechanisms of neuronal injury in chronic cerebral ischemia. Promising interventions could potentially improve the treatment and outcomes of chronic cerebral ischemia.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115003"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461515","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":"DDAH1 deficiency exacerbates cerebral vascular endothelial dysfunction by aggravating BBB disruption and oxidative stress in thoracic blast-induced brain injury","authors":"Peifang Cong,&nbsp;Changci Tong,&nbsp;Shun Mao,&nbsp;Lin Shi,&nbsp;Mingxiao Hou,&nbsp;Yunen Liu","doi":"10.1016/j.expneurol.2024.114994","DOIUrl":"10.1016/j.expneurol.2024.114994","url":null,"abstract":"<div><div>As terrorist incidents and underground explosion events have become more frequent around the world, brain injury caused by thoracic blast exposure has been more highlighted due to its injured organ, subsequent social and economic burden. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in thoracic blast-induced brain injury remains to be explained. This study seeks to investigate the mechanism of DDAH1 on thoracic blast-induced brain injury. 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly and equally divided into control group and blast group, respectively. The integrity of blood-brain barrier (BBB) was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and asymmetric dimethylarginine (ADMA) levels were determined through ELISA. HE staining and reactive oxygen species (ROS) detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, tight junction, focal adhesion, vascular endothelial injury, and the DDAH1/ADMA/eNOS signaling pathway. DDAH1 deficiency aggravated thoracic blast-induced BBB leakage, inflammatory response, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA and IRE-α expression. Regarding cerebral vascular endothelial dysfunction, DDAH1 deficiency increased the expression of MCAM, FN1, LIMK1, VEGF, MMP9, Vimentin and N-cadherin, while lowering the expression of FMR1, Occludin, claudin-3, claudin-5, Lyn, LIMA1, Glrb, Sez6, Dystrophin, and phosphorylation of VASP. Also, DDAH1 deficiency exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Thus, we conclude that DDAH1 could prevent cerebral vascular endothelial dysfunction and related injury by inhibiting ADMA signaling and increasing eNOS activity in thoracic blast induced brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 114994"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461510","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}