{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T14:06:16Z","timestamp":1779458776680,"version":"3.53.1"},"reference-count":105,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Princess Nourah bint Abdulrahman University Researchers Supporting Project","award":["PNURSP2026R892"],"award-info":[{"award-number":["PNURSP2026R892"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Postmenopausal women are at high risk of Alzheimer\u2019s disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or\/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)\/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose\/AlCl3 (60 and 10 mg\/kg, respectively) for 42 days. Group III\u2013V: Animals were exposed to MTN (10 mg\/kg\/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX\/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or\/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-\u03b1), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-\u03b3) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD\/menopause treatment and prevention via modulating the TNF-\u03b1\/p38 MAPK\/PPAR-\u03b3\/NLRP3\/GFAP pathway.<\/jats:p>","DOI":"10.3390\/ph19050770","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physical Exercise Enhances Melatonin Effect in D-Galactose\/Aluminum Chloride-Induced Alzheimer\u2019s Disease of Ovariectomized Rats: Irisin Induction Associated with Upregulation of PPAR-\u03b3\/IGF-1\/BDNF and Decreasing TNF-\u03b1\/p38-MAPK\/NLRP3\/GFAP Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Ghada A.","family":"Badawi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Arish Branch, Arish 45511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2050-3852","authenticated-orcid":false,"given":"Rawan S.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Arish Branch, Arish 45511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3723-2213","authenticated-orcid":false,"given":"Jawza A.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanaa A.","family":"El-Masry","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University-Arish Branch, Arish 45511, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala F.","family":"Zaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3495-3451","authenticated-orcid":false,"given":"Sherehan M.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 11571, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Frozza, R.L., Lourenco, M.V., and De Felice, F.G. 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