Experimental Neurology最新文献

{"title":"Daily intranasal resveratrol-conjugated gold nanoparticles administration promotes neuroprotection and improves neurological outcome in the R6/2 mouse model of Huntington's disease","authors":"Emanuela Paldino ,&nbsp;Emiliano Montalesi ,&nbsp;Marco Fiocchetti ,&nbsp;Flavia Dioguardi ,&nbsp;Iole Venditti ,&nbsp;Elena Olivieri ,&nbsp;Maria Marino ,&nbsp;Francesca R. Fusco","doi":"10.1016/j.expneurol.2026.115639","DOIUrl":"10.1016/j.expneurol.2026.115639","url":null,"abstract":"<div><div>Pan-apoptosis and involvement of the inflammatory process are the hallmarks of Huntington's disease (HD). Inflammation currently represents one of the potential therapeutic targets for slowing and fighting the pathological phenotype of HD. The immunomodulatory properties of natural compounds, such as resveratrol, have been demonstrated in various disease models and human clinical trials. In the present study, we evaluated the neuroprotective and anti-inflammatory effects of the daily intranasal administration of resveratrol-conjugated gold nanoparticles in awake R6/2 mice, the genetic animal model of HD. Transgenic mice were treated daily with resveratrol-conjugated gold nanoparticles (0.1 mg/kg/day) starting from 5 weeks of age corresponding to the prodromal stage of the disease. After sacrifice, histological and immunofluorescence studies were performed. We found that resveratrol treated R6/2 mice survived longer and displayed a significant partial recovery of motor performance compared with R6/2 mice that received the nanoparticles with vehicle. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and modulation of microglial reaction revealed a neuroprotective effect of resveratrol conjugated gold nanoparticles. Resveratrol provided a significant increase of neuroglobin, a neuroprotective globin, along with activated CREB and BDNF in the mice medium spiny neurons, accompanied by a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings showed that nanoparticles loaded with a specific compound which acts on the mutated protein intranuclear inclusions and inflammatory components may represent a valid therapeutic strategy in slowing down the symptoms of HD neurodegeneration.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115639"},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922537","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":"2026-01-07","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":"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":"2026-01-06","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":"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":"2026-01-02","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}

{"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":"2026-01-01","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":"Towards zebrafish models of migraine","authors":"Yubo Xiao ,&nbsp;Zichen Li ,&nbsp;Haojun Yao ,&nbsp;Yimeng Wang ,&nbsp;Ruyue Bai ,&nbsp;Zhili Yu ,&nbsp;Gaomuyi Wang ,&nbsp;Zhixuan He ,&nbsp;Jingbo Yang ,&nbsp;Jiale Chu ,&nbsp;Yixuan Pang ,&nbsp;Qiuyin Li ,&nbsp;Jiahao Cui ,&nbsp;Longen Yang ,&nbsp;Adam Michael Stewart ,&nbsp;Valentina N. Perfilova ,&nbsp;Clement Napo ,&nbsp;Murilo S. de Abreu ,&nbsp;Allan V. Kalueff","doi":"10.1016/j.expneurol.2025.115627","DOIUrl":"10.1016/j.expneurol.2025.115627","url":null,"abstract":"<div><div>Second among global disability causes, migraine is a severely debilitating neurological disorder that affects over 1 billion people. Recognized clinically for millennia, migraine exhibits complex multifactorial pathogenesis, whose mechanisms, risk factors, and therapy remain poorly understood. This also necessitates robust animal models that recapitulate this disorder. Complementing rodent models, the zebrafish (<em>Danio rerio</em>) is a commonly used organism in neuroscience research. Can these fish be used to study pathophysiology of migraine? Here, we discuss the developing utility of these fish for modeling migraine-like conditions and the potential for high-throughput pharmacological testing of its therapies. Critically evaluating the existing challenges of modeling migraine in zebrafish, we also outline potential future lines of research in this field.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115627"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145891723","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":"Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights","authors":"Amritpal Kaur ,&nbsp;Shareen Singh ,&nbsp;Manjinder Singh ,&nbsp;Pragati Silakari ,&nbsp;Ashi Mannan ,&nbsp;Sukriti Vishwas ,&nbsp;Puneet Kumar ,&nbsp;Vetriselvan Subramaniyan ,&nbsp;Thakur Gurjeet Singh","doi":"10.1016/j.expneurol.2025.115634","DOIUrl":"10.1016/j.expneurol.2025.115634","url":null,"abstract":"<div><div>In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β₂₅_–₃₅. In-silico docking studies revealed that DMB exhibits a high binding affinity for key proteins implicated in both AD and diabetes, including insulin receptors, leptin receptors, protein tyrosine phosphatase 1B (PTP1B), HMG-CoA reductase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Molecular dynamics simulations confirmed the stable binding and inhibitory potential of Demethyleneberberine (DMB) against Insulin Receptor Tyrosine Kinase and AChE. Pharmacological network analysis indicated that DMB modulates multiple pathways involved in metabolic and cognitive decline, suggesting its promise as a therapeutic candidate for insulin resistance-induced AD. Neurobehavioral assessments demonstrated that DMB significantly (<em>p</em> &lt; 0.001) improved cognitive function, ameliorated metabolic disruptions (elevated blood glucose and insulin levels), and normalized pro-inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin 1-beta (IL-1β)) and oxidative stress parameters (Thiobarbituric Acid Reactive Substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Additionally, DMB reduced levels of AD-related biomarkers, including BACE-1 (β-secretase 1), amyloid-β, and acetylcholinesterase, indicating its capacity to mitigate oxidative stress and amyloidogenesis. This multidisciplinary approach, integrating in vivo and in-silico methodologies, provides a comprehensive understanding of DMB's neuroprotective effects and underscores its potential as a therapeutic agent for both AD and diabetes.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115634"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892330","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":"Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice","authors":"Ruixue Zheng ,&nbsp;Xueyun Liu ,&nbsp;Zhenge Liao ,&nbsp;Runjie Wan ,&nbsp;Gengbin Qiu ,&nbsp;Min Li ,&nbsp;Chunzhi Tang ,&nbsp;Runjin Zhou ,&nbsp;Juxian Song","doi":"10.1016/j.expneurol.2025.115637","DOIUrl":"10.1016/j.expneurol.2025.115637","url":null,"abstract":"<div><div>Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers—including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns—persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115637"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892349","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":"Apelin-13 attenuates microglia-mediated neuroinflammation following intracerebral hemorrhage via targeting JAK2/STAT3 signaling pathway","authors":"Pingping Guo ,&nbsp;Jingjing Li ,&nbsp;Xiangyu Zhang ,&nbsp;Qingli Wang ,&nbsp;Yang Liu ,&nbsp;Huizhen Zhou ,&nbsp;Yun Chen ,&nbsp;V. Wee Yong ,&nbsp;Mengzhou Xue","doi":"10.1016/j.expneurol.2025.115633","DOIUrl":"10.1016/j.expneurol.2025.115633","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation is a critical contributor to secondary brain injury and subsequent neurological decline after intracerebral hemorrhage (ICH). Apelin-13, the most bioactive isoform of the endogenous G protein-coupled receptor (GPCR) ligand, exhibits protective roles in multiple neurological disorders. Nevertheless, its therapeutic effects and underlying mechanisms in neuroinflammation following ICH remain elusive.</div></div><div><h3>Methods</h3><div>In vivo, ICH was induced in mice with collagenase type VII, followed by intracerebroventricular injection of Apelin-13. In vitro, BV2 microglia were pretreated with Apelin-13 overnight, followed by lipopolysaccharide (LPS) stimulation. To investigate the mechanistic role of Apelin-13, we employed specific shRNA for APJ knockdown and the selective JAK2/STAT3 inhibitor WP1066 for pathway blockage. Western blotting and immunofluorescence assays were applied to assess JAK2/STAT3 signaling activation and pro-inflammatory mediator expression.</div></div><div><h3>Results</h3><div>Apelin-13 significantly decreased hematoma volume and mitigated neurological impairments in ICH mice. Correspondingly, both in vivo and in vitro studies confirmed its efficacy in attenuating microglia-mediated neuroinflammation. Mechanistically, Apelin-13 significantly suppressed JAK2/STAT3 signaling pathway in LPS-stimulated BV2 microglia. This suppression was reversed by APJ knockdown, verifying the necessity of the Apelin-13/APJ interaction. Furthermore, combining WP1066 with Apelin-13 significantly enhanced its anti-inflammatory effects, as evidenced by a more pronounced reduction in p-JAK2/p-STAT3 levels and pro-inflammatory cytokine secretion. Finally, the inhibition of the microglial JAK2/STAT3 pathway by Apelin-13 was also confirmed in the perihematomal brain tissues of ICH mice.</div></div><div><h3>Conclusions</h3><div>Apelin-13 attenuated brain injury after ICH by suppressing microglia-mediated neuroinflammation through APJ receptor-dependent inhibition of the JAK2/STAT3 pathway.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115633"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882228","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":"Role of A-delta low threshold mechanoreceptors and tropomyosin receptor kinase B plasticity in at-level aversive pain after spinal cord injury","authors":"Shangrila Parvin,&nbsp;Kyeongran Jang,&nbsp;Sandra M. Garraway","doi":"10.1016/j.expneurol.2025.115628","DOIUrl":"10.1016/j.expneurol.2025.115628","url":null,"abstract":"<div><div>The mechanisms of neuropathic pain after spinal cord injury (SCI) are not fully understood, although spinal and peripheral processes are involved. Maladaptive tropomyosin receptor kinase-B (TrkB) signaling has been implicated in pain hypersensitivity after SCI. A-delta-low threshold mechanoreceptors (Aδ-LTMRs) innervate the hairy skin and normally signal directional touch and are identified by their preferential TrkB expression. This study investigated whether Aδ-LTMRs play a role in at-level pain after thoracic contusion SCI. Using a modified light-dark chamber conditioned place aversion (CPA) paradigm, we assessed chamber preferences and transitions between chambers in response to mechanical stimulation, and optogenetic stimulation of Aδ-LTMRs in the trunk skin of adult TrkB^Cre mice of both sexes. Respiratory rates (RRs) were monitored at baseline and during truncal stimulation. The expression of brain-derived neurotrophic factor (BDNF), TrkB and pERK1/2 in the lesioned spinal cord and skin, and histological changes in Aδ-LTMRs in trunk skin were assessed. In addition, electrophysiological studies examined changes in Aδ-LTMRs membrane and firing properties, and response to bath-applied 7, 8-dihydroxyflavone (7,8-DHF), a TrkB agonist. The results showed that whereas brush stimulation evoked an aversive response at 4 weeks post-SCI that was accompanied by increased RRs, targeted stimulation of Aδ-LTMRs produced an aversive response 7 weeks post-SCI. SCI increased BDNF, TrkB and pERK1/2 expression in the skin, and augmented 7,8-DHF-induced inward current in Aδ-LTMRs. Together, these results suggest that plasticity of Aδ-LTMR, including an increase in TrkB signaling in the periphery, contribute to at-level affective pain following chronic SCI in adult mice.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"398 ","pages":"Article 115628"},"PeriodicalIF":4.2,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882229","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}