Experimental Neurology最新文献

{"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":"2026-04-01","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":"The metabolic reprogramming of lactate in the nervous system","authors":"Yu Gu,&nbsp;Botao Zhang,&nbsp;Chunyan Lei,&nbsp;Yanjiao Guan,&nbsp;Binger Fan,&nbsp;Wenyan Xu,&nbsp;Ansong Jin,&nbsp;Qionghua Deng,&nbsp;Ruolong Xue,&nbsp;Xinglong Yang,&nbsp;Xiaoyan Zhu","doi":"10.1016/j.expneurol.2026.115643","DOIUrl":"10.1016/j.expneurol.2026.115643","url":null,"abstract":"<div><div>Lactate, a critical energetic substrate and signaling molecule in the central nervous system (CNS), plays a pivotal role in maintaining neurophysiological homeostasis and driving the pathogenesis of neurodegenerative disorders through metabolic reprogramming. Herein, this review systematically summarizes recent progress in molecular mechanisms governing lactate metabolic reprogramming as well as its multiple biological functions in the central nervous system. Under physiological conditions, lactate regulates energy distribution via the astrocyte-neuron lactate shuttle, while mediates neural communication through receptors including G Protein-Coupled Receptor 81 and N-Methyl-<span>d</span>-Aspartate Receptor, thereby modulating synaptic plasticity and memory consolidation. In neurodegenerative pathologies (such as Alzheimer's and Parkinson's diseases), dysregulated lactate reprogramming is observed in the form of dynamic lactate imbalance, altered expression of monocarboxylate transporters and lactate dehydrogenase, and defective mitochondrial energy coupling. These perturbations further enhance neuronal damage by triggering neuroinflammation and perturbing epigenomic homeostasis (e.g., histone lactylation). Critical knowledge gaps remain unresolved: (1) The temporal dynamics of lactate flux during disease progression remain uncharacterized; (2) The spatial heterogeneity of lactate distribution across brain nuclei and its regulatory mechanisms are debated; (3) Consensus is lacking regarding functional alterations of core lactate metabolic components; and (4) The precise signaling cascades through which lactate modulates neurodegeneration require elucidation. By integrating contemporary research on central nervous system lactate reprogramming, this work provides novel perspectives on neurodegenerative disease mechanisms and establishes a theoretical framework for developing targeted therapeutic strategies that modulate lactate metabolism.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115643"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973431","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":"NFKBIZ mediates neuroprotection and maintains blood-brain barrier integrity in cerebral ischemia/reperfusion via STAT3-regulated Nrf2/ARE signaling","authors":"Cheng Huang ,&nbsp;Xiaocong Mo ,&nbsp;Ying Liu ,&nbsp;Di Hu ,&nbsp;Cun Li ,&nbsp;Yuan Zhao ,&nbsp;Shuxin Wang ,&nbsp;Jinjun Xia ,&nbsp;Xiaoyan Chen ,&nbsp;Wei Sun ,&nbsp;Rui Xu","doi":"10.1016/j.expneurol.2026.115638","DOIUrl":"10.1016/j.expneurol.2026.115638","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a leading cause of adult disability and mortality worldwide. It is characterized by a complex series of cellular and molecular events that lead to neuronal injury and disruption of the blood-brain barrier (BBB). The BBB plays a crucial role in maintaining brain homeostasis, and its disruption during IS exacerbates secondary brain injury. However, the molecular mechanisms that preserve BBB integrity and provide neuroprotection remain poorly understood. In this study, we used mRNA sequencing to identify genes differentially expressed in IS models. To investigate the role of NFKBIZ in BBB maintenance, we conducted additional in vitro and in vivo experiments. Mechanistic studies focused on the STAT3-mediated Nrf2/ARE signaling pathway, and metabolomic profiling was used to identify metabolites associated with NFKBIZ activity. Our findings indicate that NFKBIZ is essential for maintaining BBB integrity. Overexpression of NFKBIZ reduced ischemic injury and preserved BBB function, while its downregulation significantly worsened neurological deficits and BBB damage. The STAT3-Nrf2/ARE axis, a critical pathway for antioxidant defense, was activated by NFKBIZ, contributing to its protective effects. Furthermore, metabolomic analysis identified a set of metabolites linked to NFKBIZ function, providing insight into the underlying biological mechanisms. This study underscores the potential of NFKBIZ as a therapeutic target for neuroprotection and BBB preservation in IS, suggesting new avenues for developing treatments to improve outcomes in stroke patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115638"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145943025","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":"Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives","authors":"Yue Zhang ,&nbsp;Liuyi Chen ,&nbsp;Jiaqin Jin ,&nbsp;Ying Xin ,&nbsp;Junyu Wang ,&nbsp;Anren Zhang","doi":"10.1016/j.expneurol.2025.115631","DOIUrl":"10.1016/j.expneurol.2025.115631","url":null,"abstract":"<div><div>Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115631"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888581","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":"FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease","authors":"Xiaoxiao Chen ,&nbsp;Hanbing Yao ,&nbsp;Shuqing Ma ,&nbsp;Hong Zhu ,&nbsp;Yujia Xu ,&nbsp;Yun Zhu ,&nbsp;Yaozhe Ying ,&nbsp;Luhui Wang ,&nbsp;Qiongying Zhang ,&nbsp;Chenfei Zheng ,&nbsp;Ying Zhou ,&nbsp;Zhiqian Tong ,&nbsp;Kate Huang ,&nbsp;Yangping Shentu","doi":"10.1016/j.expneurol.2025.115630","DOIUrl":"10.1016/j.expneurol.2025.115630","url":null,"abstract":"<div><div>Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1–42) (Aβ₁_–₄₂) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ₁_–₄₂-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115630"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892333","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":"Sleep biomarkers of sudden unexpected death in epilepsy: Data from the Kv1.1 mouse model","authors":"Jun Wang,&nbsp;Rama Maganti","doi":"10.1016/j.expneurol.2025.115625","DOIUrl":"10.1016/j.expneurol.2025.115625","url":null,"abstract":"<div><div>Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, often occurring during sleep and lacking reliable predictive biomarkers. Here we used the Kv1.1^−/− mouse model of SUDEP to examine sleep-related biomarkers. Kv1.1^−/− and wild-type mice were implanted with electroencephalography (EEG) and electromyography (EMG) electrodes for continuous video-EEG recording. Vigilance states were scored in 4-s epochs, and spectral power was analyzed across frequency bands. Sleep homeostasis (SH) was assessed by: a) the decay of slow-wave activity (SWA; 0.5–4 Hz) during NREM sleep, b) SWA increase with prior wakefulness, and c) NREM and SWA rebound following sleep deprivation (SD). Kv1.1^−/− mice exhibited spontaneous seizures of varying frequency. Compared to wildtypes, Kv1.1^−/− mice had reduced time in NREM and REM sleep, that were worse on days with seizures (<em>p</em> &lt; 0.001). The diurnal oscillation of NREM and REM was impaired in Kv1.1^−/− mice regardless of seizures. SH was abnormal in Kv1.1^−/− mice with absence of SWA decay during lights-on when mice sleep (<em>p</em> = 0.002) and no increase in SWA with wakefulness after sleep onset (<em>p</em> = 0.005). In Kv1.1^−/− mice SWA remained unchanged in 10-day recordings with no SD (<em>p</em> = 0.22) or as mortality approached in the SD group (<em>p</em> = 0.15). Furthermore, sleep deprivation (SD) resulted in rebound increase NREM sleep (<em>p</em> &lt; 0.0001) and SWA (<em>p</em> = 0.01) in wild-types but not in Kv1.1^−/− mice. These findings suggest that abnormalities in SH may serve as candidate biomarkers of SUDEP. The data also support translational studies to develop sleep-targeted interventions to reduce SUDEP risk.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115625"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843531","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":"Machine learning for discovery of clinical pain biomarkers following spinal cord injury","authors":"Roxana Florea ,&nbsp;Ki-Soo Jeong ,&nbsp;Carl Y. Saab","doi":"10.1016/j.expneurol.2026.115649","DOIUrl":"10.1016/j.expneurol.2026.115649","url":null,"abstract":"<div><div>Chronic pain is highly prevalent in patients with spinal cord injury (SCI) and further degrades the quality of life in individuals already struggling with somatic, motor, and autonomic deficits. The management of SCI pain is challenging, mainly due to the lack of reliable, FDA-approved diagnostics, effective therapies, and incomplete understanding of the underlying mechanisms. These limitations have led to increased efforts dedicated to the identification of objective pain biomarkers. However, the FDA has yet to approve a physiologically relevant biomarker for the assessment of pain in populations with SCI. Given the multidimensional nature of pain, there is increasing recognition that composite biomarkers are needed. In this paper, we review several candidate pain signatures and discuss how the inclusion of multi-modal features such as self-reported questionnaires and behavioural measures should also be considered in the identification of comprehensive biomarkers of SCI pain. Since multi-modal, large-scale data presents a particular computational challenge, we further argue that AI and ML approaches enable novel combinatorial designs of SCI pain biomarkers. The advantages of AI and ML methods, which continue to evolve at a rapid pace, include computational efficiency, discovery of latent or embedded patterns in complex data architectures, personalized diagnostics, and minimization of potential bias. We also caution against over-reliance on physiological or neural imaging features that ignore the demographic, motivational, emotional, cognitive and cultural dimensions of pain, while advocating for AI/ML models with improved interpretability.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115649"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973429","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 deep brain stimulation attenuates parkinsonism progression in a neurotoxin-induced Parkinson's disease mouse model","authors":"Miguel Cesar Merino-Ruiz ,&nbsp;Jair Trapé Goulart ,&nbsp;Gabriely dos Santos Penha ,&nbsp;Ingrid Araújo de Santana ,&nbsp;Márcia Renata Mortari","doi":"10.1016/j.expneurol.2025.115567","DOIUrl":"10.1016/j.expneurol.2025.115567","url":null,"abstract":"<div><div>Deep brain stimulation (DBS) is an effective symptomatic therapy for Parkinson's disease (PD). Although unproven in humans, animal studies suggest that DBS, when applied beyond the acute phase of parkinsonism induction, may be neuroprotective. This study investigated motor responses and neuroprotection resulting from DBS initiated 24 h after induction of dopaminergic terminal loss via intrastriatal injection of 6-hydroxydopamine (6-OHDA) in mice. For that, three groups were analyzed: 6-OHDA/DBS-ON (<em>n</em> = 6) and 6-OHDA/DBS-OFF (<em>n</em> = 8), which received ipsilateral-to-lesion subthalamic nucleus (STN) DBS, implanted immediately after neurotoxin infusion, and Naive (<em>n</em> = 5), without interventions. 6-OHDA/DBS-ON received DBS for 4 days, 3  hours per day. The protocol began on day zero (D0). From D1 to D3, the Cylinder test was conducted. On D4, the Rotarod test was performed immediately before stimulation. Body mass was recorded daily until D4 and again on D7, before euthanasia. Tyrosine Hydroxylase (TH) immunohistochemistry was used to assess nigral neuronal loss and dopaminergic axon density in the striatum. The 6-OHDA/DBS-ON group showed less pronounced body mass loss from D0 to D4: −5.92 % (<em>p</em> = 0.22) vs. −18.04 % in 6-OHDA/DBS-OFF (<em>p</em> = 0.03). Additionally, during the 4 days of the protocol, the 6-OHDA/DBS-ON group exhibited a 3.88-fold superior impaired-limb use (<em>p</em> = 0.006) and a 17.14-fold improvement in Rotarod performance (<em>p</em> = 0.02). At the time of euthanasia (D7), the 6-OHDA/DBS-ON group had 82 % more nigral neurons (<em>p</em> = 0.03) and an 18.8 % higher lesioned/healthy striatal TH+ optical density ratio (<em>p</em> = 0.02). Altogether, the results indicate that early DBS attenuates disease progression and may contribute to neuroprotection in potential future premotor PD diagnosis scenarios.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115567"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596344","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":"TET3 SUMOylation enhances neuronal DNA damage repair and neuroprotection after ischemic stroke","authors":"Ye Pang ,&nbsp;Hui Huang ,&nbsp;Guangsheng Wang ,&nbsp;Guangci Xu ,&nbsp;Shiyuan Gu ,&nbsp;Danyang Liu ,&nbsp;Shuming Huang ,&nbsp;Wenqi Mao ,&nbsp;Yuning Liu ,&nbsp;Fengqi Zhang ,&nbsp;Yushan Hu ,&nbsp;Guiyun Cui ,&nbsp;Xingzhi Wang","doi":"10.1016/j.expneurol.2025.115566","DOIUrl":"10.1016/j.expneurol.2025.115566","url":null,"abstract":"<div><div>Ischemic stroke causes significant neuronal DNA damage, but the mechanisms regulating DNA repair remain unclear. This study investigates the role of Ten-eleven translocase 3 (TET3) in DNA damage repair and its potential neuroprotective effects in ischemic stroke. Here we show that the TET3 protein level was significantly increased in the peri-infarct cortex of mice with transient middle cerebral artery occlusion (tMCAO). Knockdown of the TET3 gene significantly worsened neurological deficits and increased infarct volume in tMCAO mice, while TET3 overexpression exhibited the opposite effects and significantly enhanced neuronal DNA damage repair. Mechanistically, SUMO2-specific conjugation of TET3 at lysine residues K1188 and K1397 enhanced its nuclear localization, protein stability, and neuronal 5hmC levels. Furthermore, SUMOylated TET3 effectively reduced DNA damage and improved neurological outcomes following ischemic stroke, whereas a SUMO site-deficient mutant failed to confer these protective effects. Our study reveals a novel mechanism by which SUMOylated TET3 regulates neuronal DNA damage repair in ischemic stroke, strongly suggesting that upregulating TET3 SUMOylation in neurons may provide a promising therapeutic strategy to facilitate stroke recovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115566"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622714","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":"Inhibition of the TRPM4 channel by 9-PH attenuates hippocampal endothelial injury induced by sleep deprivation and the subsequent neuroinflammation and neurological dysfunction","authors":"Hao Yang ,&nbsp;Sirou Huang ,&nbsp;Yiwen Ma ,&nbsp;Yichen Lu ,&nbsp;Yuan Chai","doi":"10.1016/j.expneurol.2025.115584","DOIUrl":"10.1016/j.expneurol.2025.115584","url":null,"abstract":"<div><div>Sleep deprivation (SD) is a significant public health concern and a recognized risk factor for cognitive impairment. While both vascular dysfunction and neuroinflammation are implicated, the mechanistic link between them remains elusive. Here, we identify a pathogenic positive feedback loop centered on endothelial transient receptor potential melastatin 4 (TRPM4) as a core driver of SD-induced pathology. We demonstrate that SD triggers an early and specific upregulation of TRPM4 in hippocampal endothelial cells, which in turn induces blood-brain barrier (BBB) disruption, characterized by tight junction loss and perivascular edema. This endothelial injury promotes the release of high-mobility group box 1 (HMGB1), which activates microglial TLR4–NF-κB signaling and neuroinflammation. Crucially, we provide direct evidence that microglia-derived inflammatory mediators feed back to upregulate endothelial TRPM4 expression in an NF-κB-dependent manner, thereby establishing a self-sustaining TRPM4–HMGB1–NF-κB loop. Pharmacological inhibition of TRPM4 with 9-phenanthrol (9-PH) following SD onset effectively disrupted this cycle, preserving BBB integrity, suppressing microglial activation and neuronal apoptosis, and rescuing hippocampal-dependent cognitive function. These protective effects were associated with concurrent downregulation of the HMGB1–TLR4–NF-κB axis. Our findings establish endothelial TRPM4 as a master initiator and amplifier of SD-induced neurovascular unit injury, revealing the TRPM4–HMGB1–NF-κB loop as a promising therapeutic target for mitigating the cognitive consequences of sleep loss.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115584"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687145","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}