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Rats were fed with high\u2010fat\/high\u2010fructose (HF\/Hfr) diet during the study period (17\u00a0weeks) and received one injection of streptozotocin (STZ) (25\u00a0mg\/kg) after 8\u00a0weeks of starting the study. Diabetic (T2D) rats were treated with donepezil (4\u00a0mg\/kg; p.o.) or vehicle for 8\u00a0weeks after STZ injection. The influence of donepezil on AD\u2010related behavioral, biochemical, and neuropathological changes was investigated in T2D rats. Treatment of diabetic rats with donepezil led to a significant decrease in both amyloid\u2010\u03b2 deposition and the raised hippocampal activity of cholinesterase (ChE). It significantly increased the suppressed glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). It also improved cognitive dysfunction in the passive avoidance and the Morris water maze tests. However, donepezil treatment did not significantly decrease the elevated levels of P\u2010tau, caspase\u20103, GSK\u20103\u03b2, MDA, TNF\u2010\u03b1, and IL\u20101\u03b2 in the hippocampus of diabetic rats. Also, it did not restore the suppressed levels of glutathione and superoxide dismutase in the brain of these rats. Moreover, donepezil did not alter the elevated serum level of glucose, insulin, and total cholesterol. These findings suggest that donepezil treatment could ameliorate learning and memory impairment in T2D rats through reversal of some of the AD\u2010related alterations, including reduction of amyloid\u2010\u03b2 burden and ChE activity as well as restoration of glutamate receptor expression. However, lack of any significant effect on P\u2010tau load, oxidative stress, neuroinflammation, and insulin resistance raises the question about the ability of donepezil to delay the development or arrest the progression of T2D\u2010induced AD and it is still a matter of debate that requires further studies.<\/jats:p>","DOI":"10.1111\/fcp.12585","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T08:06:15Z","timestamp":1593504375000},"page":"97-112","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Evaluation of the neuroprotective effect of donepezil in type 2 diabetic rats"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6462-0917","authenticated-orcid":false,"given":"Adel A.","family":"Gomaa","sequence":"first","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania M.","family":"Makboul","sequence":"additional","affiliation":[{"name":"Department of Pathology Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"El\u2010Mokhtar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and immunity Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engy A.","family":"Abdel\u2010Rahman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esraa A.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam A.","family":"Nicola","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine Assiut University Assiut Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2017.05.002"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-017-0355-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharep.2015.07.006"},{"key":"e_1_2_10_5_1","first-page":"1091","article-title":"Cholinesterase inhibitors as a disease\u2010modifying therapy for Alzheimer's disease: the anticholinergic hypothesis","volume":"3","author":"Hori K.","year":"2016","journal-title":"Austin J. 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