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Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-\u03b2 (A\u03b2) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO<jats:sub>4<\/jats:sub>intake in experimental rats. Thirty adult male Wistar rats (140\u2013160\u00a0g) were used in this study. AD was first induced in rats by CuSO<jats:sub>4<\/jats:sub>supplement to drinking water (10\u00a0mg\/L) for 14\u00a0weeks. The AD group received no further treatment. Oral treatment with DON (10\u00a0mg\/kg\/day), PTX (100\u00a0mg\/kg\/day), or DON\u2009+\u2009PTX for the other three groups was started from the 10th week of CuSO<jats:sub>4<\/jats:sub>intake for 4\u00a0weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like \u03b2-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated\u00a0Tau (p-tau), Clusterin (CLU), tumor necrosis factor-\u03b1 (TNF-\u03b1), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO<jats:sub>4<\/jats:sub>induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-\u03b1 were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO<jats:sub>4<\/jats:sub>-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.<\/jats:p>","DOI":"10.1007\/s12640-023-00672-1","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T03:28:52Z","timestamp":1697081332000},"page":"546-558","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer\u2019s Disease-Like Neurodegeneration in Rats"],"prefix":"10.1007","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8167-7563","authenticated-orcid":false,"given":"Mohamed M.","family":"Elseweidy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4841-7115","authenticated-orcid":false,"given":"Mohamed","family":"Mahrous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sousou I.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4974-9701","authenticated-orcid":false,"given":"Mohamed A.","family":"Shaheen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4747-7095","authenticated-orcid":false,"given":"Nahla N.","family":"Younis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,12]]},"reference":[{"key":"672_CR1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4103\/ijpvm.IJPVM_170_19","volume":"11","author":"Z Akbari","year":"2020","unstructured":"Akbari Z, Reisi P, Torkaman-Boutorabi A, Farahmandfar M (2020) Effect of pentoxifylline on apoptotic-related gene expression profile, learning and memory impairment induced by systemic lipopolysaccharide administration in the rat hippocampus. 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