{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:17:58Z","timestamp":1787591878897,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["RSPD2023R812"],"award-info":[{"award-number":["RSPD2023R812"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington\u2019s disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg\/kg\/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory\/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened A\u03b242 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1\/Nrf2\/HO-1 axis. Moreover, topiramate inactivated GSK-3\u03b2 and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK\/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.<\/jats:p>","DOI":"10.3390\/ph16091214","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:26:52Z","timestamp":1693297612000},"page":"1214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Targeting Autophagy, Apoptosis, and SIRT1\/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-6901","authenticated-orcid":false,"given":"Hany H.","family":"Arab","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"},{"name":"Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Eid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania","family":"Yahia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5567-6169","authenticated-orcid":false,"given":"Shuruq E.","family":"Alsufyani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-0499","authenticated-orcid":false,"given":"Ahmed M.","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3726-0386","authenticated-orcid":false,"given":"Azza A. K.","family":"El-Sheikh","sequence":"additional","affiliation":[{"name":"Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany W.","family":"Darwish","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 11451, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed A.","family":"Saad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Y.","family":"Al-Shorbagy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab Emirates"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa A.","family":"Masoud","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119031","DOI":"10.1016\/j.lfs.2021.119031","article-title":"Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK\/mTOR and Nrf2\/HO-1 pathways","volume":"269","author":"Arab","year":"2021","journal-title":"Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.3233\/JAD-200282","article-title":"Heavy Metals Exposure and Alzheimer\u2019s Disease and Related Dementias","volume":"76","author":"Bakulski","year":"2020","journal-title":"J. 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