{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T01:33:43Z","timestamp":1768008823469,"version":"3.49.0"},"reference-count":118,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:00:00Z","timestamp":1760832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Heart and Stroke Foundation of Canada","award":["G-16-00014633"],"award-info":[{"award-number":["G-16-00014633"]}]},{"name":"Saskatchewan Health Research Foundation Collaborative Innovation and Development Grant","award":["SHRF CID #5146"],"award-info":[{"award-number":["SHRF CID #5146"]}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"crossref","award":["NSERC DG: RGPIN-2015-03850"],"award-info":[{"award-number":["NSERC DG: RGPIN-2015-03850"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008920","name":"University of Saskatchewan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008920","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Glutamate receptors represent a potential target for neuroprotection in neurodegenerative neurological conditions. Perampanel, a non-competitive \u03b1-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, is clinically approved for the management of epilepsy. Perampanel\u2019s neuroprotective effects have been reported in global and focal cerebral ischemia models, but the cellular mechanisms remain incompletely understood. Therefore, we studied the potential neuroprotective effects of perampanel in rats using the pial vessel disruption (PVD) stroke model, an established focal cortical non-reperfusion ischemic stroke model. Perampanel was given once intraperitoneally (3 mg\/kg body weight) 1 h after PVD surgery and repeated on days 2\u20133 post-surgery. On the fourth day post PVD, animal behavioral assays and imaging, biochemical, and electrophysiological analyses were performed. Compared to vehicle control, perampanel in PVD-treated rats significantly inhibited hippocampal neurodegeneration and long-term potentiation deficits. Perampanel also attenuated PVD-induced motor deficits, depressive\/anxiety-like behaviors, and hippocampal-dependent cognitive impairment. In addition, perampanel prevented the PVD-induced downregulation of surface-expressed GluA1 and GluA2 AMPARs and increased phosphorylation of GluA1 at S831 and S845. Molecular docking analysis revealed perampanel binding to transmembrane regions M1, M3 and M4 of GluA1 and GluA2 subunits. Together, our results show that perampanel attenuated PVD-induced neurodegeneration and behavioral deficits by blocking AMPARs and decreasing GluA1 and GluA2 internalization. In addition, this study shows the neuroprotective potential of perampanel through the inhibition of neuroinflammation mediated by activated microglia and astrocytes following cerebral ischemia. This study is the first to evaluate perampanel in the pial vessel disruption model of ischemia without reperfusion, a clinically relevant stroke paradigm that differs fundamentally from middle cerebral carotid artery occlusion and photothrombosis stroke models.<\/jats:p>","DOI":"10.3390\/cells14201628","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:23:34Z","timestamp":1760952214000},"page":"1628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Non-Competitive AMPA Receptor Antagonist Perampanel Inhibits Ischemia-Induced Neurodegeneration and Behavioral Deficits in Focal Cortical Pial Vessel Disruption Stroke Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7354-4605","authenticated-orcid":false,"given":"Michael G.","family":"Zaki","sequence":"first","affiliation":[{"name":"Department of Surgery, Neuroscience Research Cluster, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2013-1601","authenticated-orcid":false,"given":"Mohamed Taha","family":"Moutaoufik","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahboubeh","family":"Pordeli","sequence":"additional","affiliation":[{"name":"Department of Surgery, Neuroscience Research Cluster, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohan","family":"Babu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4527-7404","authenticated-orcid":false,"given":"Changiz","family":"Taghibiglou","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5058-7087","authenticated-orcid":false,"given":"Francisco S.","family":"Cayabyab","sequence":"additional","affiliation":[{"name":"Department of Surgery, Neuroscience Research Cluster, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0140-6736(16)30962-X","article-title":"Stroke","volume":"389","author":"Hankey","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0140-6736(96)04453-4","article-title":"Progression of ischaemic stroke and excitotoxic aminoacids","volume":"349","author":"Castillo","year":"1997","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1161\/CIR.0000000000000558","article-title":"Heart Disease and Stroke Statistics\u20142018 Update: A Report From the American Heart Association","volume":"137","author":"Benjamin","year":"2018","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1161\/STROKEAHA.122.040073","article-title":"Projected Global Trends in Ischemic Stroke Incidence, Deaths and Disability-Adjusted Life Years From 2020 to 2030","volume":"54","author":"Pu","year":"2023","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1161\/STROKEAHA.117.020587","article-title":"Posttreatment National Institutes of Health Stroke Scale Is Superior to the Initial Score or Thrombolysis in Cerebral Ischemia for 3-Month Outcome","volume":"49","author":"Jeong","year":"2018","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e281","DOI":"10.1093\/brain\/awu065","article-title":"Thrombolysis in acute ischaemic stroke","volume":"137","author":"Vidale","year":"2014","journal-title":"Brain J. 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