Experimental Neurology最新文献

{"title":"Effect of hypoglycemia on the diameter of cerebral vasculature in vivo and cerebral ischemia-reperfusion injury in mice","authors":"Wesley R. Evans ,&nbsp;Natalie Grosek ,&nbsp;William Wisen ,&nbsp;Lokanatha Oruganti ,&nbsp;Raed Ageeli ,&nbsp;Ricardo Mostany ,&nbsp;Prasad V.G. Katakam","doi":"10.1016/j.expneurol.2025.115605","DOIUrl":"10.1016/j.expneurol.2025.115605","url":null,"abstract":"<div><h3>Objective</h3><div>Pharmacotherapy for diabetes mellitus (DM) with anti-diabetic agents such as insulin carries the risk of acute hypoglycemia (&lt;70 mg/dl). Recent evidence suggests that patients exposed to hypoglycemia have worsened health outcomes than DM patients who do not experience hypoglycemia. The objective of the study is to determine the impact of hypoglycemia on ischemia-reperfusion injury to brain in mice and investigate the role of underlying cerebral vascular and hemodynamic mechanisms.</div></div><div><h3>Methods</h3><div>We subjected male C57Bl/6 J mice to either single episode (acute hypoglycemia) or five episodes (recurrent hypoglycemia, RH) insulin-induced hypoglycemia or saline injection (RS, control). We employed two-photon microscopy in isoflurane anesthetized animals with cranial windows over somatosensory cortex for imaging cerebral vasculature. We induced cerebral ischemia-reperfusion injury in mice by transient middle cerebral occlusion using filament method.</div></div><div><h3>Results</h3><div>We found that acute hypoglycemia but not RH promotes increase in cerebral capillary diameter in vivo. However, experimental stroke induced 24 h after the final episode of RH was found to increase infarct volume in mice, suggesting that RH promotes long-lasting vulnerability to ischemic brain injury beyond the duration of hypoglycemia. Diameter of capillaries was found to increase over the reperfusion time course similarly in RH and RS groups. In contrast, animals subjected to RH displayed increased normalized RBC flux over the reperfusion period when compared to RS group.</div></div><div><h3>Conclusions</h3><div>Acute hypoglycemia induces changes to cerebral vascular diameter; however, RH promotes increased ischemic injury and altered hemodynamics of arterial blood flow without altering the diameter of cerebral penetrating arteries or capillaries.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115605"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833412","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":"Mechanism of human umbilical cord mesenchymal stem cells in the treatment of germinal matrix hemorrhage–intraventricular hemorrhage","authors":"Chang Xu ,&nbsp;Shulin Liu ,&nbsp;Khalil U.R. Rahman ,&nbsp;Shenglin Chen ,&nbsp;Guozhong Zhang ,&nbsp;Ye Song ,&nbsp;Peng Li","doi":"10.1016/j.expneurol.2025.115607","DOIUrl":"10.1016/j.expneurol.2025.115607","url":null,"abstract":"<div><div>Germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is a severe complication frequently occurring in preterm infants, often resulting in permanent neurological impairment and persistent functional deficits. Human umbilical cord-derived mesenchymal stem cells have shown significant promise as a therapeutic approach in neonatal brain injury due to their robust paracrine effects, multipotent differentiation potential, and minimal immunogenic properties. The protective roles of human umbilical cord mesenchymal stem cells (hUC-MSCs) involve multiple synergistic pathways, such as suppressing neuroinflammatory responses, inducing apoptotic processes, stimulating neurogenesis and angiogenesis, and enhancing blood-brain barrier integrity. Additionally, hUC-MSCs and their extracellular vesicles (EVs) confer protective benefits through the secretion and delivery of bioactive substances, including cytokines and microRNAs (miRNAs), which can alleviate brain damage and subsequently enhance motor and cognitive outcomes. Although further large-scale clinical investigations are required to validate their effectiveness, current preclinical and animal studies provide preliminary evidence affirming the safety profile and therapeutic efficacy of hUC-MSCs treatment as an innovative strategy for managing GMH-IVH.</div></div><div><h3>Literature search strategy</h3><div>We conducted a systematic literature search to identify relevant publications. The primary databases were PubMed and Web of Science, with the search period extending through October 2025. The search combined the following keywords and, where applicable, MeSH terms: “Germinal matrix hemorrhage,” “Intraventricular hemorrhage,” “GMH-IVH,” “White matter injury,” “Hydrocephalus,” “mesenchymal stem cells,” “MSC,” “umbilical cord,” “mechanism,” “therapy,” “neuroprotection,” and “clinical trials.” We also searched <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> for ongoing or completed trials of MSCs for neonatal brain injury. The selection prioritized original research, high-quality reviews, and meta-analyses. After an initial title-and-abstract screening, full texts of potentially relevant articles were examined. Studies offering the most significant insight into the mechanisms of hUC-MSC therapy in GMH-IVH were chosen for in-depth discussion in this review.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115607"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833480","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":"Investigating the therapeutic potential of nasal administration of mitochondria on blood-brain barrier integrity and vasogenic brain Edema in a rat ischemic stroke model","authors":"Nooshin Sadeghian ,&nbsp;Hamdollah Panahpour ,&nbsp;Mohammad Reza Alipour ,&nbsp;Fereshteh Farajdokht ,&nbsp;Javad Shadman","doi":"10.1016/j.expneurol.2025.115609","DOIUrl":"10.1016/j.expneurol.2025.115609","url":null,"abstract":"<div><div>Mitochondrial dysfunction is an early and critical factor in the development of ischemic stroke. This study investigated the therapeutic potential of intranasally delivered mitochondria to reduce vasogenic cerebral edema and protect blood-brain barrier (BBB) integrity in a rat model of ischemic stroke. Male rats underwent 60 min of middle cerebral artery occlusion to induce stroke and then received daily intranasal mitochondrial treatment (750 μg/50 μl) for two days. Cerebral edema was measured by the wet/dry method, and BBB permeability was assessed using Evans blue dye extravasation. Mitochondrial function was evaluated by assessing mitochondrial swelling, mitochondrial membrane potential (MMP), succinate dehydrogenase (SDH) activity, and reactive oxygen species (ROS) production. Protein levels of matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), and markers of apoptosis were examined by immunofluorescence. The treatment significantly reduced infarct size, improved sensorimotor function, decreased cerebral edema, and preserved BBB integrity. These benefits correlated with improved mitochondrial function—demonstrated by reduced swelling and ROS, and restoration of MMP and SDH activity. Additionally, mitochondrial therapy lowered apoptosis and decreased expression of MMP-9 and ICAM-1. These findings suggest that intranasal mitochondrial administration mitigates cerebral edema and BBB disruption after ischemic stroke. This protective effect is likely achieved by enhancing mitochondrial function and lowering levels of inflammation-related proteins, suggesting a promising neuroprotective strategy targeting mitochondrial dysfunction in stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115609"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833403","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":"Abnormal upregulation of SPP1 promotes fibrotic scar after peripheral nerve repair (FS-PNR) by driving M2 macrophage polarization","authors":"Jingyuan Fan ,&nbsp;Zhe Li ,&nbsp;Nan Zhang ,&nbsp;Shuolin Wang ,&nbsp;Canbin Zheng ,&nbsp;Qingtang Zhu ,&nbsp;Honggang Wang ,&nbsp;Jian Qi ,&nbsp;Liwei Yan","doi":"10.1016/j.expneurol.2025.115612","DOIUrl":"10.1016/j.expneurol.2025.115612","url":null,"abstract":"<div><div>Fibrotic scar after peripheral nerve repair (FS-PNR) hinder axon regeneration and functional recovery. However, the mechanism underlying FS-PNR formation remains elusive. SPP1, a glycoprotein known to promote fibrosis in multiple organ systems, was abnormally upregulated in human peripheral nerve fibrotic scar tissues, though its cellular functions in FS-PNR were undefined. Using single- nucleus RNA sequencing, we confirmed SPP1 upregulation in FS-PNR patients and identified repair Schwann cells (rSCs) as its primary cellular source, with macrophages as key targets. To investigate this axis, we established an animal model replicating clinical FS-PNR pathology, validated by histopathological and functional assessments. Notably, SPP1 elevation correlated with increased M2 macrophage infiltration within fibrotic scars. Genetic ablation of SPP1 in mice significantly reduced scar formation and improved functional outcomes. Transcriptomic analysis revealed that SPP1 depletion promoted macrophage M1 polarization. Further <em>in vitro</em> studies demonstrated that SPP1 drives fibrogenesis by inducing macrophage M2 polarization. Together, our findings implicate SPP1 as a novel mediator of FS-PNR pathology <em>via</em> rSCs-macrophage crosstalk.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115612"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814284","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":"Lipopolysaccharide-binding protein: The missing link in sleep and inflammation","authors":"Ye Qin ,&nbsp;Lei Sun ,&nbsp;Xuyuan Fan ,&nbsp;Jie Chen ,&nbsp;Jun Zhang ,&nbsp;Longfei Du","doi":"10.1016/j.expneurol.2025.115610","DOIUrl":"10.1016/j.expneurol.2025.115610","url":null,"abstract":"<div><div>Sleep disorders represent a major global health issue, and their association with systemic low-grade inflammation has become increasingly clear. Lipopolysaccharide-binding protein (LBP), a key mediator of the immune response to gut microbiota-derived endotoxins, has emerged as a potential regulatory molecule in inflammation-related sleep disorders. Elevated LBP levels are closely linked to a variety of sleep disorders. LBP induces sleep dysregulation through multiple mechanisms, including mediating peripheral and central immune inflammation, disrupting neurotransmitter balance, and perturbing biological rhythms. Both preclinical and clinical studies have observed abnormal LBP changes in different sleep disorder models. LBP serves as a critical interface molecule connecting peripheral immune activation and central sleep regulation. Targeting the LBP signaling pathway provides a new perspective for understanding and treating immune-mediated sleep disorders, yet its translational application still faces challenges. This review systematically summarizes clinical and preclinical studies on the role of LBP in sleep, neuroimmunity, and related diseases, aiming to clarify the potential pathophysiological mechanisms of LBP in sleep disorders and explore its prospects as a therapeutic target.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115610"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833498","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":"From first responders to outcome modulators: The evolving paradigm of neutrophils in ischemic stroke and thrombolysis","authors":"Jiawei Wu ,&nbsp;Zheng Huang ,&nbsp;Siqi Chang ,&nbsp;Zihao Peng ,&nbsp;Zixuan Fang ,&nbsp;Guangxia Ni ,&nbsp;Yawen Xia","doi":"10.1016/j.expneurol.2025.115611","DOIUrl":"10.1016/j.expneurol.2025.115611","url":null,"abstract":"<div><div>Neutrophils are increasingly recognized as pivotal contributors to the ischemic stroke cascade, influencing disease progression, thrombolysis outcomes, and patient prognosis. Epidemiological evidence consistently links neutrophil counts with the incidence of ischemic stroke. Pathophysiologically, neutrophils play critical roles in disrupting blood-brain barrier, amplifying inflammatory responses, and promoting thrombotic processes. Understanding their role is crucial for developing targeted therapies to improve stroke outcomes. This review focuses on the role of neutrophils in ischemic stroke, covering epidemiology, pathophysiological mechanisms, historical perspectives, interactions with rt-PA thrombolysis, clinical implications, controversies, challenges, and future directions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115611"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833500","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":"ELAVL1 interacts with APP and promotes Aβ-induced apoptosis in Alzheimer's disease by activating Bcl-2/Bax signaling","authors":"Jun Fu ,&nbsp;Chengjie Ding ,&nbsp;Wenqing Li ,&nbsp;Jiali Lei ,&nbsp;He Wang ,&nbsp;Lingfei Meng ,&nbsp;Xiaoya Lin ,&nbsp;Weiyuan Chen ,&nbsp;Hongchang Gao","doi":"10.1016/j.expneurol.2025.115613","DOIUrl":"10.1016/j.expneurol.2025.115613","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, with hallmark pathological features including Aβ deposition and tau protein hyperphosphorylation. These pathological alterations are particularly prominent in the Prefrontal Cortex (PFC) and exert profound effects on cognitive function. The present study aimed to reveal key proteins in the PFC and provide insight into their potential mechanisms of action in AD. Accordingly, proteomic analysis was conducted to profile differential proteins in 5 × FAD mice, followed by <em>in vivo</em> and <em>in vitro</em> validation of core proteins through AAV-mediated interference of target gene expression. Furthermore, transcriptomics and molecular biology techniques were employed to confirm the underlying mechanisms of action of core proteins in AD. The results demonstrated that ELAVL1 was significantly upregulated in the PFC of AD mice. Behavioral experiments revealed that inhibition of ELAVL1 expression markedly improved long-term memory in AD mice. Immunostaining and Western blot analyses confirmed that suppressing ELAVL1 expression alleviated Aβ1–42 deposition and apoptosis. <em>In vitro</em> experiments indicated that knocking down ELAVL1 significantly reduced the apoptotic response of SH-SY5Y cells induced by Aβ1–42 and APP/Swe cells. Transcriptomic analysis further revealed that ELAVL1 regulates Aβ1–42-induced apoptosis <em>via</em> activation of the Bcl-2/Bax pathway. Notably, immunofluorescence co-localization staining and pull-down assays confirmed that ELAVL1 directly interacts with APP. Collectively, these findings provide valuable insights into the molecular mechanisms underlying AD and suggest ELAVL1 as a promising therapeutic target for AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115613"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833495","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":"Subacute cathodal transcranial direct current stimulation rescues secondary thalamic neurodegeneration after cortical stroke in mice","authors":"Stefan J. Blaschke ,&nbsp;Heiko Backes ,&nbsp;Susan Vlachakis ,&nbsp;Nora Rautenberg ,&nbsp;Seda Demir ,&nbsp;Dirk Wiedermann ,&nbsp;Markus Aswendt ,&nbsp;Gereon R. Fink ,&nbsp;Michael Schroeter ,&nbsp;Maria A. Rueger","doi":"10.1016/j.expneurol.2025.115604","DOIUrl":"10.1016/j.expneurol.2025.115604","url":null,"abstract":"<div><div>Transcranial direct current stimulation (tDCS) is a clinically promising neuromodulatory therapy, capable of promoting function and motor recovery after stroke. Beyond the primary stroke lesion, remote networks disturbances, e.g., stroke-induced secondary neurodegeneration (SND), are related to long-term disabilities. Under the hypothesis that tDCS promotes recovery by supporting neuroprotection, we investigated the effects of tDCS on thalamic SND after stroke.</div><div>Three days after cortical stroke, induced by photothrombosis, cathodal tDCS over the lesioned cortex was performed daily for ten days (39.6 kC/m²). SND, i.e., neuronal loss, and inflammation in the ipsilesional thalamus were evaluated ex vivo 28 days after stroke. Parameters of functional thalamic network integration measured by resting-state functional magnetic resonance imaging (rs-fMRI) were conducted longitudinally. To assess the effects of tDCS on glucose metabolism, positron emission tomography (PET) was performed after a similar tDCS regimen in healthy mice.</div><div>Repetitive tDCS decreased the ipsilateral thalamic glucose metabolism in unlesioned animals. Four weeks after cortical stroke, secondary glial scaring was found in the ipsilesional thalamus, its extent correlating to the cortical lesion size (R² = 0.54, <em>p</em> &lt; 0.001). Notably, while it did not affect glial scaring, tDCS reduced thalamic neurodegeneration by over 60 % (<em>p</em> &lt; 0.05), being reflected by parameters of functional thalamic integration as assessed by rs-fMRI. Additionally, tDCS downregulated the pro-inflammatory polarization of microglia.</div><div>Overall, tDCS ameliorated the stroke-induced remote SND, in parallel to mitigating sustained neuroinflammation. Thus, the data show that tDCS exerts previously unknown effects on remote brain regions after stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115604"},"PeriodicalIF":4.2,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833450","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":"Meprin β elevates hippocampal soluble Aβ in the APP/V717I mouse model","authors":"Maximilian Keller ,&nbsp;Celine Gallagher ,&nbsp;Liana Marengo ,&nbsp;Kira Bickenbach ,&nbsp;Ulrich Schmitt ,&nbsp;Mohammad Abukhalaf ,&nbsp;Andreas Tholey ,&nbsp;Simon Kreiselmaier ,&nbsp;Christoph Becker-Pauly ,&nbsp;Thomas Mittmann ,&nbsp;Claus U. Pietrzik","doi":"10.1016/j.expneurol.2025.115600","DOIUrl":"10.1016/j.expneurol.2025.115600","url":null,"abstract":"<div><div>The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115600"},"PeriodicalIF":4.2,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803435","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":"Mechanistic study on Lnc-Gstm5 regulation of the SUV39H1/H3K9me3 axis in hyperbaric oxygen-mediated suppression of inflammatory response following spinal cord injury","authors":"Shaoting Jia ,&nbsp;Mo Liu ,&nbsp;Ding Nan,&nbsp;Lu Yang,&nbsp;Jing Zhang,&nbsp;Jing Yang,&nbsp;Xuehua Liu","doi":"10.1016/j.expneurol.2025.115599","DOIUrl":"10.1016/j.expneurol.2025.115599","url":null,"abstract":"<div><div>Hyperbaric oxygen (HBO) suppresses the inflammatory response following spinal cord injury (SCI). However, the underlying detailed mechanisms are still to be clarified. Here we explored the mechanism of long non-coding RNA (lncRNA) glutathione s-transferase mu 5 (Gstm5) regulating NF-κB signaling pathway in HBO-mediated suppression of inflammatory response following SCI. In the current study, SCI cell model was developed with lipopolysaccharides (LPS)-induced BV2 cells and processed with HBO treatment, si-NC, and si-Lnc-Gstm5. Lnc-Gstm5, NF-κB p65, IL-1β，IL-6, TNF-a, suppressor of variegation 3–9 homolog 1 (SUV39H1), histone 3 lysine 9 trimethylation (H3K9me3), YTH domain containing 2 (YTHDC2) expression level were measured. The mice SCI model was generated and treated with HBO treatment, shRNA-Lnc-Gstm5. Lnc-Gstm5 was identified and BMS score, histopathological injury score, and inflammatory factors were evaluated. We found that HBO suppresses inflammatory response through up-regulating Lnc-Gstm5 level in a manner of YTHDC2-dependent m6A modification. Lnc-Gstm5 recruits SUV39H1 to up-regulate H3K9me3 expression level and suppresses NF-κB signaling pathway by reducing p65 phosphorylation. HBO suppresses the inflammatory response via YTHDC2/Lnc-Gstm5/SUV39H1/H3K9me3/NF-κB axis following SCI in mice. These results reveal a Lnc-Gstm5-driven epigenetic regulation mechanism, and targeting Lnc-Gstm5 represents a promising therapeutic strategy for SCI patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115599"},"PeriodicalIF":4.2,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793704","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}