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Neurosci."],"abstract":"<jats:p>Background: Epilepsy is a central nervous system disorder characterized by abnormal neuronal discharges in the brain. The purpose of this study was to investigate the protective effects of a caspase-1 inhibitor on glial hyperactivation and neuronal apoptosis in epilepsy. Methods: A pilocarpine-induced status epilepticus (SE) mouse model was established. Belnacasan (VX765), a caspase-1 inhibitor, was administered intraperitoneally. ELISA was used to detect inflammatory cytokines interleukin (IL)-1\u03b2, IL-6, and tumor necrosis factor-alpha (TNF-\u03b1) in peripheral blood. Immunohistochemistry and transmission electron microscopy were used to evaluate glial activation and neuronal damage in the hippocampus. Western blotting was performed to detect caspase-1 and Gasdermin D N-terminal (GSDMD-N) expression. In vitro, primary glial cells were stimulated with lipopolysaccharide (LPS), and the effects of glial conditioned medium on HT22 neuronal apoptosis were assessed using cell counting kit-8 (CCK-8) and flow cytometry. Results: In vivo experiments showed that, as epilepsy progressed, the levels of pro-inflammatory cytokines IL-1\u03b2 and IL-6 in peripheral blood were significantly increased, consistent with findings in patients with epilepsy. At 21 days after epilepsy induction, the numbers of hyperactivated microglia and astrocytes increased significantly and exhibited activation-related features such as organelle swelling, whereas neuronal numbers were markedly reduced and displayed cytological features of apoptosis. VX765 significantly alleviated seizure frequency and severity in epileptic mice and attenuated peripheral blood levels of IL-1\u03b2 and IL-6, hippocampal caspase-1 activity, glial hyperactivation, and neuronal apoptosis. In vitro experiments demonstrated that glial conditioned medium (CMG) promoted apoptosis of HT22 neurons by regulating Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) expression, whereas VX765 alleviated HT22 neuronal apoptosis by inhibiting the secretion of inflammatory factors from glial cells. Conclusions: These results indicate that inhibiting glial cell hyperactivation and neuroinflammation via caspase-1 inhibition may represent a potential therapeutic strategy for epilepsy.<\/jats:p>","DOI":"10.31083\/jin49777","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T08:26:51Z","timestamp":1780129611000},"source":"Crossref","is-referenced-by-count":0,"title":["The Neuroprotective Role of a Caspase-1 Inhibitor Against Apoptosis via Inhibition of Glial Hyperactivation in a Mouse Model of Epilepsy"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6670-5867","authenticated-orcid":true,"given":"Hui","family":"Cai","sequence":"first","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Bengbu Medical University, 233000 Bengbu, Anhui, China"},{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6938-0256","authenticated-orcid":true,"given":"Xinran","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1341-6084","authenticated-orcid":true,"given":"Xuerui","family":"Zhuo","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2251-469X","authenticated-orcid":true,"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Bengbu Medical University, 233000 Bengbu, Anhui, China"},{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4010-5520","authenticated-orcid":true,"given":"Hao","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9885-2100","authenticated-orcid":true,"given":"Yiming","family":"Sun","sequence":"additional","affiliation":[{"name":"Pharmacy Department, The First Affiliated Hospital of Bengbu Medical University, 233000 Bengbu, Anhui, China"},{"name":"School of Pharmacy, Bengbu Medical University, 233030 Bengbu, Anhui, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Devinsky O, Vezzani A, O\u2019Brien TJ, Jette N, Scheffer IE, de Curtis M, et al. 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