Experimental Neurology最新文献

{"title":"Age and sex dependent hippocampal neuronal hyperactivity in Alzheimer model mice","authors":"E. Hegnet,&nbsp;S. Häkli,&nbsp;H. Koivisto,&nbsp;P.O. Miettinen,&nbsp;N. Jin,&nbsp;I. Gureviciene,&nbsp;H. Tanila","doi":"10.1016/j.expneurol.2025.115632","DOIUrl":"10.1016/j.expneurol.2025.115632","url":null,"abstract":"<div><div>Both seizures and epileptiform discharges have been reported in various amyloid plaque- forming mouse models of Alzheimer's disease (AD). These mice also show premature mortality possibly related to epileptic seizures. Yet, the relationship between epileptic manifestations and amyloid pathology remains elusive. We utilized deltaFosB as a marker for sustained neuronal hyperactivity to localize the epileptic focus and compared it with age and sex differences in premature mortality between APP/PS1, 5xFAD and wildtype littermate mice and epileptiform discharges (EDs) during sleep in cortex and hippocampus. APP/PS1 mice showed elevated FosB/deltaFosB (shortly FosB) staining in the dentate granule (DG) cells and CA1-CA3 pyramidal cells. These were also the origins of identified epileptiform discharges (EDs) in LFP recordings. APP/PS1 mice showed much higher premature mortality than 5xFAD mice, females more than males. FosB staining intensity in APP/PS1 mice was robustly elevated compared to wildtype mice and peaked at 3 months of age. In contrast, FosB intensity in 5xFAD was lower than in wildtype mice at 1 and 3 months of age, showing a modest elevation at 10 months. In APP/PS1 mice between 1.5 and 3 months of age, the DG amyloid load correlated positively with FosB intensity. Furthermore, the DG FosB intensity showed a positive correlation with the frequency of EDs during sleep. These findings suggest that FosB staining intensity can be used as a proxy for local epileptiform activity in AD model mice and help unveil cellular and molecular basis of AD related neuronal hyperactivity and epilepsy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115632"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892378","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":"Biochanin A exerts neuroprotective effects in Parkinson's disease both in vivo and in vitro by improving mitochondrial dysfunction through the Sirt1 signaling pathway","authors":"Shuxiang Tian ,&nbsp;Mingguang Niu ,&nbsp;Qian Qian,&nbsp;Kexian Zhang,&nbsp;Han Yang,&nbsp;Yang Xiao,&nbsp;Xinyue Jin,&nbsp;Yanyan Yin","doi":"10.1016/j.expneurol.2025.115636","DOIUrl":"10.1016/j.expneurol.2025.115636","url":null,"abstract":"<div><div>The accumulation of reactive oxygen species (ROS) leading to mitochondrial dysfunction is the pathological characteristics underlying the damage to dopaminergic neurons in the substantia nigra (SN) of Parkinson's disease (PD). Therefore, through improving mitochondrial dysfunction may be a potential strategy for PD treatment. Biochanin A (Bioch A), as a natural isoflavone phytoestrogen, has been implicated in studies for its therapeutic potential in neurodegenerative diseases. However, the precise molecular mechanisms by which it modulates PD-related neuronal damage remain unclear, limiting its clinical translational application. This study focuses on the neuroprotective mechanism of Bioch A, systematically revealing the key pathways and regulatory mechanisms through which it exerts its neuroprotective effects in PD by targeting mitochondrial dysfunction. By establishing lipopolysaccharide (LPS)-induced PD model mice and tumor necrosis factor-α (TNF-α)-induced SH-SY5Y cell models, combined with in vivo and in vitro experiments confirmed that Bioch A significantly alleviates dopaminergic neuronal damage by downregulating ROS levels, modulating adenosine triphosphate (ATP) production, promoting mitochondrial biogenesis, and improving abnormal mitochondrial dynamics. More importantly, this study has for the first time revealed that the Sirt1 pathway is a core target for Bioch A in regulating mitochondrial dysfunction. Furthermore, Bioch A promotes mitochondrial biogenesis by activating the Sirt1 pathway and reduces apoptosis levels by promoting mitochondrial fusion. In conclusion, this study provides novel experimental evidence for Bioch A's regulation of mitochondrial dysfunction, establishing the Sirt1 pathway as a key neuroprotective target. This discovery paves the way for Bioch A's clinical translation and targeted therapeutic research in PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115636"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896397","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":"Letter to the editor: “Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures” by Kakulavarapu V. Rama Rao, et al.","authors":"W. Brad Hubbard ,&nbsp;Rania Abutarboush ,&nbsp;Stephen T. Ahlers ,&nbsp;Pamela J. VandeVord","doi":"10.1016/j.expneurol.2025.115602","DOIUrl":"10.1016/j.expneurol.2025.115602","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115602"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843581","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":"2026-04-01","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":"Astrocytic TPK1 mitigates amyloid pathology via TFEB-mediated endocytosis","authors":"Shu-Zhen Zhang ,&nbsp;Yuan Ma ,&nbsp;Yu Ding ,&nbsp;Yan-Qing Yin ,&nbsp;Bing-Wei Wang ,&nbsp;Gang Hu ,&nbsp;Jia-Wei Zhou","doi":"10.1016/j.expneurol.2026.115640","DOIUrl":"10.1016/j.expneurol.2026.115640","url":null,"abstract":"<div><div>Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and progressive neurodegeneration. Deregulation of glial cell activity plays an important role in the amyloid pathology. However, it is still unclear how changes in astrocytes contribute to Aβ deposition and clearance in AD. Here, we showed that deficiency of astrocytic thiamine pyrophosphokinase 1 (<em>Tpk1</em>), exacerbated Aβ burden leading to exacerbated spatial memory deficits in a mouse model of AD. While selective overexpression of <em>Tpk1</em> in astrocytes ameliorated cognitive decline and significantly reduced hippocampal and cortical Aβ plaque burden. Enhanced <em>Tpk1</em> expression augmented astrocyte endocytic capacity. Mechanistically, <em>Tpk1</em>-promoted endocytic activity depended on the activation of transcription factor EB (TFEB)-mediated pathways. Collectively, our findings demonstrate that astrocytic TPK1 mitigates cognitive impairment in 5xFAD mice by upregulating TFEB expression, thereby enhancing astrocyte-mediated engulfment and degradation of neurotoxic aggregates, including Aβ. This study suggests that astrocytic TPK1/TFEB pathway is a promising target for developing disease-modifying AD therapies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115640"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931587","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":"Chronic effects of traumatic brain injury and the impact of biperiden treatment in a male rat model","authors":"Viviam Sanabria ,&nbsp;Matheus B. Braga ,&nbsp;Simone Romariz ,&nbsp;Christiane Gimenes ,&nbsp;Michele Longoni Calió ,&nbsp;Maira Licia Foresti ,&nbsp;Luiz Eugênio Mello ,&nbsp;Beatriz M. Longo","doi":"10.1016/j.expneurol.2025.115626","DOIUrl":"10.1016/j.expneurol.2025.115626","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) disrupts brain function and may lead to post-traumatic epilepsy (PTE), a long-term complication. Anticholinergic drugs, such as biperiden, have shown potential in modulating neural plasticity. This study evaluated whether biperiden treatment influences motor and cognitive recovery, seizure susceptibility, and neurovascular and inflammatory responses in rats subjected to the lateral fluid percussion injury (LFPI) model. Adult male Wistar rats underwent LFPI or sham surgery and were treated with saline or biperiden (8 mg/kg) administered intraperitoneally every 8 h for 10 days, starting 6 h after trauma. Neuromotor battery tests were assessed over 28 days, spatial memory at 30 days using the Barnes Maze, and seizure susceptibility was tested with pentylenetetrazol (PTZ) at 90 days after trauma as a second hit. Plasma samples were collected 10 days after trauma for Single Molecular Array (SIMOA) analysis of trauma biomarkers, neurofilament light chain (NfL), and total tau. Histological and immunofluorescence analyses were conducted at 91 days. TBI significantly increased plasma NfL levels compared to the Naive group, indicating neuronal damage. Animals that underwent LFPI and were treated with saline solution were called TBI-SAL group, while animals that underwent LFPI and were treated with biperiden solution were called TBI-BIP group. TBI-SAL group exhibited memory impairments and random search strategies in the Barnes Maze. Both TBI groups (those treated with saline and with biperiden) exhibited higher seizure susceptibility to PTZ at 30 mg/kg, but biperiden slightly reduced seizure intensity. Histological analyses revealed larger lesion volumes, reduced NeuN expression in hippocampal regions (CA1, CA3), and altered astrocytic and microglial morphology in the TBI-SAL group. Notably, biperiden treatment promoted vascular remodeling, characterized by an increase in vessel density, in the motor cortex and hippocampal regions, suggesting potential modulation of post-traumatic neuroinflammation. Biperiden enhanced vascular remodeling and partially mitigated long-term histopathological changes after TBI, though its protective effects on cognitive and seizure-susceptibility responses were limited. These findings highlight biperiden's potential to influence vascular and inflammatory responses in the injured brain.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115626"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882227","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":"Spatiotemporal multi-omics profiling of secondary brain injury after intracerebral hemorrhage in an optimized autologous blood-induced mouse model with human tissue validation","authors":"Yang Du ,&nbsp;Guangshuo Li ,&nbsp;Yijun Lin ,&nbsp;Zeqiang Ji ,&nbsp;Yiwei Shi ,&nbsp;Xiaojing Zhang ,&nbsp;Na Zhou ,&nbsp;Jia Zhang ,&nbsp;Kaijiang Kang ,&nbsp;Xingquan Zhao ,&nbsp;Liheng Bian","doi":"10.1016/j.expneurol.2026.115650","DOIUrl":"10.1016/j.expneurol.2026.115650","url":null,"abstract":"<div><h3>Background</h3><div>Secondary brain injury (SBI) following intracerebral hemorrhage (ICH) involves complex molecular events such as oxidative stress, inflammation, and immune cell infiltration. Understanding their spatiotemporal patterns is essential for identifying therapeutic targets and optimal intervention windows.</div></div><div><h3>Methods</h3><div>We optimized an autologous blood-induced ICH mouse model and performed neuroimaging, behavioral testing, histological evaluation, and transcriptomic and proteomic analyses across multiple time points (Days 1, 3, 5, 8, and 12). Time-resolved analyses focused on dynamic changes in SBI-related pathways, including oxidative stress, ferroptosis, leukocyte migration, neutrophil extracellular trap (NET) formation, and phagocytic–lysosomal activity, with spatial validation by immunofluorescence and histology. Model refinements reduced blood coagulation and leakage, improving procedural success and reproducibility. In addition, imaging and perihematomal tissue from a patient 66 h after ICH onset were examined for comparison.</div></div><div><h3>Results</h3><div>Principal component and clustering analyses revealed a time-dependent molecular trajectory, with rapid early transcriptional changes followed by delayed but sustained protein-level responses. Markers of oxidative stress and ferroptosis (HMOX1, FTH1), adhesion molecules (VCAM1, CD11b), and phagocytic activity (CD68, CTSD) displayed distinct temporal and spatial expression patterns. NET formation peaked between Days 3 and 5 and then gradually declined. Human ICH tissue demonstrated similar activation of oxidative, inflammatory, and phagocytic pathways.</div></div><div><h3>Conclusions</h3><div>This study delineates the spatiotemporal dynamics of key pathways and molecules involved in secondary brain injury after ICH, revealing stage-specific molecular features and potential therapeutic windows. The optimized autologous blood-induced ICH model exhibits good stability, reproducibility, and relevance to human pathology.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115650"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988827","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":"2026-04-01","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":"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":"2026-04-01","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":"Sleep deprivation attenuates acute ischemic stroke-induced hippocampal neuronal injury via the IL-38/NF-κB axis","authors":"Anlin Yue ,&nbsp;Yongfei Liu ,&nbsp;Zhongting Wang ,&nbsp;Mian Zhang ,&nbsp;Yuan Qin ,&nbsp;Zhaoyan Zhao ,&nbsp;Jingxiang Wang ,&nbsp;Shuxuan He ,&nbsp;Jiangjing Li ,&nbsp;Xude Sun ,&nbsp;Li Sun","doi":"10.1016/j.expneurol.2025.115635","DOIUrl":"10.1016/j.expneurol.2025.115635","url":null,"abstract":"<div><h3>Background</h3><div>Although epidemiological studies have identified sleep disorders as a risk factor for stroke, animal studies have yielded conflicting results regarding the impact of sleep deprivation (SD). This study aimed to investigate whether SD preconditioning can alleviate early neurological impairment following acute ischemic stroke and to explore the potential role of the anti-inflammatory cytokine interleukin-38 (IL-38) in this process.</div></div><div><h3>Methods</h3><div>Male Sprague-Dawley rats underwent 10-day SD preconditioning using a modified multi-platform method before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological function was evaluated using the Longa scoring system, while cerebral infarct volume was quantified via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histopathological changes in brain tissues were assessed through hematoxylin-eosin (H&amp;E) staining, Nissl staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The expression level of IL-38 and the status of inflammatory responses were analyzed using Western blotting, immunohistochemistry, and immunofluorescence. IL-38 knockout (IL-38 KO) rats were employed to verify the essential role of IL-38 in SD-induced neuroprotection.</div></div><div><h3>Results</h3><div>SD preconditioning significantly improved neurological function, reduced cerebral infarct volume, and decreased neuronal apoptosis in the CA1 region of the hippocampus. Notably, SD preconditioning markedly upregulated IL-38 expression, which was predominantly localized in neurons and exhibited a time-dependent increase pattern. In IL-38 KO rats, the neuroprotective effects of SD preconditioning were completely abolished, with no improvements observed in neurological scores, infarct size, or neuronal survival. Mechanistically, SD preconditioning reduced the levels of pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) and inhibited the phosphorylation of p65 in the nuclear factor-κB (NF-κB) signaling pathway, and these regulatory effects were largely dependent on IL-38.</div></div><div><h3>Conclusions</h3><div>SD preconditioning confers neuroprotection against acute ischemic stroke by upregulating IL-38 expression. IL-38 mediates this protection, at least in part, by attenuating neuroinflammation through suppression of the NF-κB signaling pathway. These findings identify IL-38 as a critical mediator of SD-induced ischemic tolerance, warranting further clinical investigation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115635"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899637","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}