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VX-765 is a potent small-molecule caspase-1 inhibitor that protects against central nervous system diseases. The present study aimed to determine the protective effects of VX-765 on \u03b2-amyloid (A\u03b2) deposition and secondary degeneration in the hippocampus as well as cognitive decline after cortical infarction. Sprague\u2013Dawley rats were used to establish a distal middle cerebral artery occlusion (dMCAO) model and randomly divided into the vehicle and VX-765 groups. Rats in the vehicle and VX-765 groups, respectively, were subcutaneously injected with VX-765 (50\u00a0mg\/kg\/d) and an isopycnic vehicle once a day for 28\u00a0days, starting 1\u00a0h after dMCAO. At the end of this 28-day period, cognitive impairment was evaluated with the Morris water maze, and secondary hippocampal damage was evaluated with Nissl staining and immunostaining methods. Neuronal damage and pyroptosis were detected by TUNEL and immunoblotting. The results revealed that VX-765 treatment ameliorated poststroke cognitive dysfunction after ischemia. VX-765 reduced A\u03b2 deposition, neuronal loss, and glial activation compared with the vehicle control. In addition, VX-765 treatment increased BDNF levels and normalized synaptophysin protein levels in the hippocampus after cortical infarction. Notably, VX-765 treatment significantly reduced the expression of the pyroptosis-related molecules caspase-1, NLRP3, apoptosis-associated speck-like protein (ASC), gasdermin D, IL-1\u03b2, and IL-18. Additionally, VX-765 significantly decreased the numbers of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 (cC3) and enhanced the levels of Bcl-2 and Bcl-xl after ischemia. Inflammatory pathways, such as the NF-\u03baB and mitogen-activated protein kinase (MAPK) pathways, were inhibited by VX-765 treatment after ischemia. These findings revealed that VX-765 reduced A\u03b2 deposition, pyroptosis, and apoptosis in the ipsilateral hippocampus, which may be associated with reduced secondary degeneration and cognitive decline following focal cortical infarction.<\/jats:p>","DOI":"10.1007\/s12031-022-02088-6","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T06:05:06Z","timestamp":1669615506000},"page":"2389-2397","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["VX-765 Alleviates \u03b2-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats"],"prefix":"10.1007","volume":"72","author":[{"given":"Dawei","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihui","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-7098","authenticated-orcid":false,"given":"Yubin","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"2088_CR1","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1002\/jnr.24130","volume":"96","author":"L Alvarez-Arellano","year":"2018","unstructured":"Alvarez-Arellano L, Pedraza-Escalona M, Blanco-Ayala T, Camacho-Concha N, Cortes-Mendoza J, Perez-Martinez L et al (2018) Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to beta-amyloid peptide accumulation. 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