Experimental Neurology最新文献

{"title":"Microglial dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions","authors":"Mahir Azmal ,&nbsp;Jibon Kumar Paul ,&nbsp;Fatema Sultana Prima ,&nbsp;A.N.M. Shah Newaz Been Haque ,&nbsp;Meghla Meem ,&nbsp;Ajit Ghosh","doi":"10.1016/j.expneurol.2025.115374","DOIUrl":"10.1016/j.expneurol.2025.115374","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a severe neurodegenerative condition characterized by progressive cognitive decline and behavioral changes. These symptoms are primarily driven by the accumulation of amyloid-beta (Aβ) plaques, tau tangles, and persistent neuroinflammation. Microglia, the brain's resident immune cells, play a crucial role in the disease's progression. Initially, these cells protectively respond to Aβ deposits, working to clear plaques and support neuronal health. However, prolonged activation of microglia leads to a transition from a neuroprotective state to a pro-inflammatory one, ultimately contributing to neuronal damage and worsening disease progression. This review explores the molecular mechanisms responsible for microglial dysfunction in AD, with a particular emphasis on key inflammatory pathways, including NF-κB, MAPK, and TLR4 signaling. These pathways drive the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which further amplify neuroinflammation, disrupt synaptic plasticity, and contribute to neuronal loss. Additionally, emerging therapeutic strategies aimed at modulating microglial activity to reduce neuroinflammation and enhance Aβ clearance are examined. A key focus is placed on the future of AD research, emphasizing the importance of longitudinal studies to gain a deeper understanding of how microglia contribute to disease progression over time. The review also highlights the potential of personalized medicine, which seeks to tailor treatments based on an individual's unique genetic and environmental risk factors. Notably, genetic predispositions such as the APOE4 allele, along with environmental influences like air pollution and chronic infections, are identified as significant modulators of microglial activity. Given the complexity of AD, a comprehensive, multi-faceted approach will be essential for advancing research and developing more effective therapeutic interventions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115374"},"PeriodicalIF":4.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144605499","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":"Elucidating the mechanistic role of Rip3 in post-thalamic hemorrhage neurological deficits","authors":"Yinggang Xiao ,&nbsp;Yaqun Li ,&nbsp;Yang Zhang ,&nbsp;Yali Ge ,&nbsp;Shuai Han ,&nbsp;Zi Wang ,&nbsp;Ju Gao ,&nbsp;Tianfeng Huang","doi":"10.1016/j.expneurol.2025.115373","DOIUrl":"10.1016/j.expneurol.2025.115373","url":null,"abstract":"<div><div>Thalamic hemorrhage (TH), a critical subtype of intracerebral hemorrhage, often leads to central post-stroke pain (CPSP) and neurological deficits, yet its molecular mechanisms remain poorly understood. This study investigated the role of Rip3 in TH pathophysiology by constructing <em>Rip3</em>-knockout (KO) mice and integrating behavioral assessments, transcriptomic sequencing, and molecular experiments. Results demonstrated that TH induced motor dysfunction, mechanical pain hypersensitivity, working memory impairment, and anxiety-like behaviors in wild-type (WT) mice, while Rip3 knockout significantly alleviated pain sensitivity and anxiety and reduced hemorrhage volume. Transcriptomic analysis identified 956 Rip3-related candidate genes, among which Tac1, Gal, and Pdyn were validated as key downstream genes through protein-protein interaction networks and experimental assays. RT-qPCR and Western blot revealed significant upregulation of these genes in WT mice post-TH, with reduced expression in KO mice. Functional enrichment analysis implicated these genes in pathways such as NEUREXINS_AND_NEUROLIGINS and DOPAMINERGIC_NEUROGENESIS. Drug prediction identified potential therapeutic candidates, including Nizatidine, Ginger Allergenic Extract, Paregoric, and Estradiol 3-Benzoate, with the latter showing promise in modulating synaptic plasticity and pain signaling. Inhibition of Pdyn and Tac1 alleviated mechanical allodynia, while all three inhibitors, including Gal's, exhibited significant anxiolytic effects in the TH-induced CPSP model. This study reveals, for the first time, a correlative link between Rip3 and post-TH neurological injury and CPSP, potentially mediated via Tac1, Gal, and Pdyn regulation, providing novel targets for therapeutic intervention. Future research should validate direct <em>Rip3</em>-gene interactions and the efficacy of predicted drugs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115373"},"PeriodicalIF":4.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595577","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":"Ischemic stroke altered the expression profiles of super enhancer RNAs in mouse brain in a sexually dimorphic manner","authors":"Hadjer Namous ,&nbsp;Vijay Arruri ,&nbsp;Thomas Galleske ,&nbsp;Raghu Vemuganti","doi":"10.1016/j.expneurol.2025.115372","DOIUrl":"10.1016/j.expneurol.2025.115372","url":null,"abstract":"<div><div>Super enhancer RNAs (seRNAs) serve as vital regulators of gene expression, yet their role in ischemic stroke remains unexplored. Using microarrays, we profiled seRNAs and their target mRNAs in the peri-infarct cortex of male and female C57BL/6 J mice at 6 h and 24 h of reperfusion after transient focal ischemia. The seRNA expression profiles altered in a temporal and sex-specific manner with a more pronounced dysregulation in males. Gene ontology analysis showed that stroke-responsive seRNA-associated mRNAs involved in critical pathways, including neurogenesis, angiogenesis, and immune responses. Weighted Gene Co-expression Network Analysis showed that the upregulated driver seRNAs are associated with leukocyte proliferation and inflammation, and the downregulated driver seRNAs are linked to nucleosome organization, RNA stability, neuronal apoptosis, and mTOR signaling after focal ischemia. Several stroke-responsive seRNAs are also observed to be associated with transcription factors. These results suggest that seRNAs are pivotal regulators of post-stroke brain damage and recovery, providing potential targets for therapeutic intervention.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115372"},"PeriodicalIF":4.6,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616912","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":"KIF23 inhibition protects against perioperative neurocognitive disorders by hindering ROS/caspase-3/GSDME-mediated pyroptosis","authors":"Shaoqun Tang ,&nbsp;Xi Yu ,&nbsp;Lei Zhang,&nbsp;Xueshan Bu,&nbsp;Wei Wang,&nbsp;Zhongyuan Xia","doi":"10.1016/j.expneurol.2025.115371","DOIUrl":"10.1016/j.expneurol.2025.115371","url":null,"abstract":"<div><div>The activation of caspase-3 and gasdermin E (GSDME)-mediated pyroptosis is a key driver of perioperative neurocognitive disorders (PND). Kinesin family member 23 (KIF23), a constituent of the kinesin superfamily of microtubule-associated motor proteins, governs NLRP3 inflammasome-mediated pyroptosis and is essential for dendritic differentiation and development. This study sought to ascertain whether KIF23 influences PND by affecting caspase-3/GSDME-dependent pyroptosis. The PND mouse model was established through laparotomy under isoflurane (Iso) anesthesia following recombinant adeno-associated virus 9 (AAV9)-mediated knockdown of KIF23, with or without the intraperitoneal administration of the caspase-3 agonist Raptinal. HT22 cells were transfected with either pcDNA3.1-KIF23 or siKIF23, followed by exposure to Iso and lipopolysaccharide (LPS). Cognitive performance, TUNEL staining, and pyroptosis-related parameters were assessed. KIF23 protein was upregulated in the hippocampus of aged mice following anesthesia and surgery. AAV9-shKIF23 ameliorated postoperative memory decline, suppressed reactive oxygen species (ROS) production and diminished the levels of cleaved caspase-3, N-GSDME, IL-1β and IL-18, which were reversed by Raptinal. KIF23 silencing enhanced neuronal viability and antioxidant capacity, blocked the cleavage of caspase-3 and N-GSDME, and repressed the release of IL-1β, IL-18, and LDH. Conversely, KIF23 overexpression exerted opposing effects on pyroptosis in response to Iso + LPS, which was abrogated by the caspase-3 inhibitor Ac-DEVD-CHO. These findings suggest that KIF23 could serve as a promising therapeutic target for PND through its positive modulation of pyroptosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"393 ","pages":"Article 115371"},"PeriodicalIF":4.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607888","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":"Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures","authors":"Kakulavarapu V. Rama Rao,&nbsp;Victor L. McLean,&nbsp;Donna M. Wilder,&nbsp;Shataakshi Dahal,&nbsp;Malavika Kattuparambil,&nbsp;Joseph B. Long,&nbsp;Venkatasivasai Sujith Sajja","doi":"10.1016/j.expneurol.2025.115375","DOIUrl":"10.1016/j.expneurol.2025.115375","url":null,"abstract":"<div><div>Blast wave (BW)-associated brain injury criteria to assess risk of Warfighters are currently inadequate due to lack a suitable animal model that does not represent human blast injury pathology. We hypothesize that animal models with brain structures more closely resemble the human brain (e.g. gyrencephalic models) could better translate to recreate and identify human blast pathology. As a one-of-a kind evaluation, this study compared the blood brain barrier (BBB) integrity, gliovascular changes and neuroinflammation in lissencephalic (rats) and gyrencephalic (ferrets) models exposed to blast waves at varying overpressures (10, 15 and 20 psig) with a validation study in non-human primates exposed to a single BW at 20 psig. BBB disruption was measured by Evans blue extravasation. The extent of gliosis in brain sections was measured by immunofluorescence analysis of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba-1), and neurodegeneration was determined by silver staining. Ferrets exposed to BW had a statistically significant increase in extravasation of Evans blue in different brain regions while a no such changes were observed in the rat model. Blast also induced a significant reactive astrogliosis and microglial activation in ferrets. NHPs exposed to a single BW at 20 psig showed a significant increase in EB extravasation in only thalamus. These results suggest that gyrencephalic brain structures may be more vulnerable to vascular disruption compared to lissencephalic models and these models may have better translatability to human blast injuries and potentially better suited to identify injury thresholds.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115375"},"PeriodicalIF":4.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580750","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":"Microglia interact with dendritic spines and regulate spine numbers after brain injury following resuscitation from a cardiac arrest","authors":"Jacob M. Basak ,&nbsp;Macy Falk ,&nbsp;Andra L. Dingman ,&nbsp;Annabelle Moore ,&nbsp;Erika Tiemeier ,&nbsp;Giulia Aimale ,&nbsp;Nidia Quillinan","doi":"10.1016/j.expneurol.2025.115364","DOIUrl":"10.1016/j.expneurol.2025.115364","url":null,"abstract":"<div><div>Cognitive dysfunction is common after global cerebral ischemic injury caused by a cardiac arrest and is likely due in part to changes in synaptic function. Increasing evidence suggests microglial cells regulate synapse architecture and activity in various pathophysiologic conditions. However, the role of microglia in mediating synaptic injury after global cerebral ischemia has not been addressed. In this study, we use a mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to evaluate changes that occur in the numbers and morphology of both dendritic spines and microglia in the hippocampus after global cerebral ischemia. We also directly evaluate the interaction between dendritic spines and microglia after CA/CPR and assess how altering microglial numbers after the injury affects spine numbers. Our findings highlight that CA/CPR results in hippocampal spine loss that occurs in parallel with an increase in microglia numbers. Morphologic analysis of microglial cells demonstrates that CA/CPR leads to acute changes in cellular structure consistent with reactivity to the ischemic injury. We also show that microglia-spine contacts increase in the period following a CA/CPR injury along with co-localization between spines and phagocytic vesicles within microglia, suggesting a potential role for microglial engulfment in mediating spine loss. Finally, we demonstrate that pharmacologic depletion of microglia with PLX5622 after CA/CPR restores spine numbers in the injured brain. Collectively, these results emphasize the important role microglia exhibit in regulating synapse numbers in the setting of a CA/CPR injury and suggest targeting microglia-synapse interactions may improve cognitive outcomes following global ischemic brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115364"},"PeriodicalIF":4.6,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580654","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":"SerpinA3N inhibits mitochondrial complex I activity to prevent neuron ferroptosis following cerebral ischemic stroke","authors":"Xiansheng Liu ,&nbsp;Gan Li ,&nbsp;Yunlu Guo ,&nbsp;Ruqi Li ,&nbsp;Shilin Yi ,&nbsp;Shenghao Ding ,&nbsp;Jieqing Wan","doi":"10.1016/j.expneurol.2025.115370","DOIUrl":"10.1016/j.expneurol.2025.115370","url":null,"abstract":"<div><div>SerpinA3N, a serine protease inhibitor, plays emerging roles in programmed cell death regulation, yet its intracellular function in neuronal ferroptosis remains unexplored. Using the multi-omic integrative analyses of the neurons from middle cerebral artery occlusion (MCAO) challenged mouse model, we found that Serpina3n-deficient mice exhibited significantly dysregulated ferroptosis signaling networks characterized by mitochondrial lipid peroxidation amplification and redox homeostasis collapse as compared to wide type mice. An arginine mutation at position 90 of Ndufs3, the catalytic core subunit of mitochondrial complex I, in HT-22 cells impaired the binding of Ndufs3 with SerpinA3N and potentiated ferroptosis of HT-22 cells following oxygen glucose deprivation/reperfusion (OGD/R). Furthermore, neuron-specific Isl1 overexpression in wide type mice or intraperitoneal injected zinc robustly upregulated the expression of SerpinA3N in neurons following MCAO. We further found that both the overexpression of Isl1 in neurons and zinc treatment could reduce infarct volume, and improve sensorimotor recovery post-stroke. These findings collectively suggest SerpinA3N as a key mitochondrial redox regulator and reveals zinc-Isl1 signaling as a promising neuroprotective target. These findings not only identified a novel role for SerpinA3N in ferroptosis but also indicated that zinc ion may be a valuable candidate for the development of a potential therapeutic approach.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115370"},"PeriodicalIF":4.6,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144557285","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 omics techniques used in perineuronal nets research","authors":"Sihan Huang ,&nbsp;Jiao Tang ,&nbsp;Xiao Wu ,&nbsp;Huan Xu ,&nbsp;Sihui Li ,&nbsp;Hongying Li ,&nbsp;Siyu Zhang ,&nbsp;Guangxin Xie ,&nbsp;Tingyu Wang ,&nbsp;Xincheng Pan ,&nbsp;Ahmad Fasih ,&nbsp;Maochun You ,&nbsp;Zhanqiong Zhong ,&nbsp;Lushuang Xie ,&nbsp;Qiaofeng Wu ,&nbsp;Shuguang Yu","doi":"10.1016/j.expneurol.2025.115369","DOIUrl":"10.1016/j.expneurol.2025.115369","url":null,"abstract":"<div><div>Neurodegenerative diseases (NDs) are progressive disorders characterized by neuronal degeneration in the central nervous system (CNS), ultimately leading to neurological dysfunction. Neurodegenerative progression is often associated with structural and functional alterations in perineuronal nets (PNNs). With the continuous advancement of sequencing technologies and omics disciplines, numerous techniques have been widely applied to studies on PNNs. Research on PNNs is beneficial for understanding the pathogenesis and clinical diagnosis of NDs and finding new drug treatment targets. In this review, we paid attention to these omics technologies used in PNNs and also summarized some alterations in PNNs in NDs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115369"},"PeriodicalIF":4.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559645","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":"Effect of activated autophagy on an animal model of vestibular migraine-like attacks","authors":"Hongyan Li ,&nbsp;Yanan Huang ,&nbsp;Qihui Chen,&nbsp;Qingling Zhai,&nbsp;Changman Zhang,&nbsp;Qijun Yu,&nbsp;Shijiao Chen,&nbsp;Changchang Ying,&nbsp;Yonghui Pan","doi":"10.1016/j.expneurol.2025.115366","DOIUrl":"10.1016/j.expneurol.2025.115366","url":null,"abstract":"<div><h3>Background</h3><div>Patients with vestibular migraine (VM) experience both dizziness and headache. Our team's previous pilot study has revealed a significant increase in the concentration of the autophagic marker P62 in the blood of VM patients. This finding indicates a close association between cellular autophagic function and VM pathogenesis.</div></div><div><h3>Objective</h3><div>In our study, our objective was to integrate the elements of dizziness and headache, thereby constructing a rat model of vestibular migraine-like attacks (VMa) that could effectively mimic the symptoms of VM. This article will conduct an in-depth exploration into the establishment of the VMa rat model and comprehensively analyze the role of autophagy within both the VMa rat model and VM patients.</div></div><div><h3>Methods</h3><div>We established the VMa rat model via intraperitoneal nitroglycerin injection and 2-h variable speed rotation. Assessed VMa rats' pain sensitivity by periorbital mechanical and tail thermal pain thresholds. Evaluated their vestibular function with MS index and balance beam experiments. Measured CGRP, c-fos, P62 and LC3-II/I proteins in TCC and VN by western blot. In clinical experiments, selected same-age patients without comorbidities based on CM and VM criteria. Determined P62 and LC3-II concentrations in peripheral plasma by ELISA. Explored the therapeutic significance of blocking PI3K/AKT/mTOR pathway and autophagy agonist intervention in VM disease.</div></div><div><h3>Results</h3><div>First, compared VMa model rats with normal SHAM group: periorbital mechanical &amp; tail thermal pain thresholds decreased, CGRP &amp; c-fos expression increased in TCC &amp; VN, MS index higher, balance beam time increased, vestibular function disturbed. LC3-II/I ratio not significantly changed but P62 expression elevated. Second, compared VM patients with normal individuals: plasma P62 concentration elevated, LC3-II/I slightly increased (not statistically significant), showing autophagy dysfunction in VM patients. Finally, in VMa rats treated with rapamycin &amp; LY294002 for prevention: periorbital mechanical &amp; tail thermal pain thresholds increased, MS index decreased, balance beam time shortened. CGRP &amp; c-fos expression reduced in TCC &amp; VN, P62 expression decreased, autophagy function normal.</div></div><div><h3>Conclusions</h3><div>The VMa rat model can be established by mimicking VM patients' dizziness and headache symptoms. It shows similar increased pain sensitivity, disrupted vestibular function, and autophagy dysfunction as in VM patients. Activating autophagy might provide prophylactic treatment for VM disease.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115366"},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552788","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":"HDAC6 inhibition enhances peroxiredoxin 1 acetylation to mitigate oxidative stress and seizure activity in focal cortical dysplasia","authors":"Sonali Kumar ,&nbsp;Ozasvi R. Shanker ,&nbsp;Sreestha Dinesh Parambath ,&nbsp;Jyotirmoy Banerjee ,&nbsp;Manjari Tripathi ,&nbsp;P. Sarat Chandra ,&nbsp;M.C. Sharma ,&nbsp;Sanjeev Lalwani ,&nbsp;Fouzia Siraj ,&nbsp;Aparna Banerjee Dixit","doi":"10.1016/j.expneurol.2025.115367","DOIUrl":"10.1016/j.expneurol.2025.115367","url":null,"abstract":"<div><h3>Background</h3><div>Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy (DRE) which is characterized by malformations of the cortex and molecular dysregulation. Despite advancements in classification and surgical interventions the pathophysiology behind it remains unclear and non-surgical treatment options remain limited. Oxidative stress, induced by imbalances of reactive oxygen species (ROS) and antioxidant defences, has been involved in the pathophysiology of FCD. This study evaluates the role of histone deacetylase 6 (HDAC6) in modulating oxidative stress and seizure activity through the acetylation status of peroxiredoxin-1 (Prdx1), a key antioxidant enzyme.</div></div><div><h3>Methods</h3><div>Cortical samples from FCD Type II patients and BCNU rat model were analysed using qRT-PCR, immunoblotting, and co-immunoprecipitation to assess the expression of HDAC6, and acetylation status of Prdx1. ROS levels were measured using dichlorofluorescin diacetate (DCFDA) assay. Pharmacological inhibition of HDAC6 using Tubastatin A (TubA) was evaluated for its effects on oxidative stress, Prdx1 acetylation, and seizure activity induced by pilocarpine.</div></div><div><h3>Results</h3><div>HDAC6 was found to be significantly upregulated in the cortical samples from FCD Type II tissues and BCNU rats. Increased HDAC6 activity reduced Prdx1 acetylation, leading to elevated ROS levels and oxidative stress. TubA treatment restored Prdx1 acetylation, reduced oxidative stress, and significantly decreased seizure frequency and increased seizure latency in the BCNU model.</div></div><div><h3>Conclusion</h3><div>This study identifies HDAC6 as a key regulator of oxidative stress and epileptogenesis in FCD through Prdx1 deacetylation. Pharmacological inhibition of HDAC6 offers a promising therapeutic strategy for managing FCD-associated epilepsy by restoring antioxidant defences and mitigating seizure activity. Further studies are warranted to explore its clinical potential.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115367"},"PeriodicalIF":4.6,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552789","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}