{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T14:00:17Z","timestamp":1778767217048,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Topiramate, a promising drug classically used for the management of neurological disorders including epilepsy and migraine, has demonstrated marked anti-inflammatory and anti-apoptotic actions in murine models of cardiac post-infarction inflammation, wound healing, and gastric\/intestinal injury. However, its potential impact on cadmium-induced testicular injury remains to be elucidated. Herein, the present study aimed to explore the effect of topiramate against cadmium-invoked testicular impairment with emphasis on the molecular mechanisms linked to inflammation, apoptosis, and autophagy. Herein, administration of topiramate (50 mg\/kg\/day, by gavage) continued for 60 days and the testes were examined by histology, immunohistochemistry, and biochemical assays. The present data demonstrated that serum testosterone, sperm count\/abnormalities, relative testicular weight, and histopathological aberrations were improved by topiramate administration to cadmium-intoxicated rats. The rescue of testicular dysfunction was driven by multi-pronged mechanisms including suppression of NLRP3\/caspase-1\/IL-1\u03b2 cascade, which was evidenced by dampened caspase-1 activity, lowered IL-1\u03b2\/IL-18 production, and decreased nuclear levels of activated NF-\u03baBp65. Moreover, curbing testicular apoptosis was seen by lowered Bax expression, decreased caspase-3 activity, and upregulation of Bcl-2. In tandem, testicular autophagy was activated as seen by diminished p62 SQSTM1 accumulation alongside Beclin-1 upregulation. Autophagy activation was associated with AMPK\/mTOR pathway stimulation demonstrated by decreased mTOR (Ser2448) phosphorylation and increased AMPK (Ser487) phosphorylation. In conclusion, combating inflammation\/apoptosis and enhancing autophagic events by topiramate were engaged in ameliorating cadmium-induced testicular impairment.<\/jats:p>","DOI":"10.3390\/ph15111402","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T04:50:43Z","timestamp":1668401443000},"page":"1402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Topiramate Reprofiling for the Attenuation of Cadmium-Induced Testicular Impairment in Rats: Role of NLRP3 Inflammasome and AMPK\/mTOR-Linked Autophagy"],"prefix":"10.3390","volume":"15","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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayat A.","family":"Abd El Aal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA), Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9034-6624","authenticated-orcid":false,"given":"El-Shaimaa A.","family":"Arafa","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates"},{"name":"Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5101-8011","authenticated-orcid":false,"given":"Ahmed M.","family":"Kabel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed H.","family":"Eid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA), Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.jes.2018.07.015","article-title":"Effects of environmental contaminants on fertility and reproductive health","volume":"77","author":"Ma","year":"2019","journal-title":"J. Environ. 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