{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:26Z","timestamp":1777376006871,"version":"3.51.4"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Alzheimer\u2019s disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid \u03b2 and intraneuronal neurofibrillary tangles in the brain. Increasing evidence shows that the disturbance of insulin signalling in the brain may contribute to the pathophysiology of Alzheimer\u2019s disease. In type 1 diabetes, these disruptions are caused by hypoinsulinemia, but in type 2 diabetes, they are caused by insulin resistance and decreased insulin secretion. Multiple studies have shown that diabetes is connected with an increased risk of acquiring Alzheimer\u2019s disease. The aim of this study was to investigate the impact of anti-diabetic agents on Alzheimer\u2019s disease progression and the levels of Alzheimer\u2019s biomarkers in a hyperglycaemic rat model, which was induced by intraperitoneal injection of streptozocin to produce insulin-deficient diabetes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Method<\/jats:title>\n<jats:p>Thirty-six male Wistar albino rats were allocated into six groups of six rats each. Group I was the negative control group. Intraperitoneal injections of streptozocin (42mg\/kg) were used once for the five experimental groups. Group II served as the positive control group. The rats in Groups III, IV, V, and VI received metformin (300mg\/kg), donepezil (10mg\/kg), insulin glargine (3 unit\/animal), and glibenclamide (10mg\/kg), respectively, for 21 days.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Inducing hyperglycaemia in rats significantly increased the levels of serum glucose, haemoglobin A1c, total cholesterol, triglycerides, high-density lipoprotein, interleukin 6, tumour necrosis factor alpha, amyloid \u03b2 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid \u03b2 42, nitric oxide, acetylcholinesterase, malondialdehyde, \u03b2 secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid \u03b2 42, total plasma tau, brain amyloid \u03b2 42, acetylcholinesterase, and malondialdehyde were observed in rats treated with metformin. In contrast, rats treated with donepezil demonstrated the greatest statistically significant reduction in serum tumour necrosis factor alpha, brain nitric oxide, and \u03b2 secretase. The levels of neurofilament light and phosphorylated microtubule-associated protein tau in the brains of rats treated with insulin glargine were significantly lower than the other treatment groups. The total cholesterol and low-density lipoprotein levels in rats treated with glibenclamide exhibited the most statistically significant reductions of all the treatment groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Metformin and donepezil, when administered at appropriate doses, were shown to successfully lower most plasma and brain biomarkers, including glucose, triglycerides, tumour necrosis factor alpha, amyloid \u03b2 42, nitric oxide, acetylcholinesterase, malondialdehyde, and \u03b2 secretase in rats suffering from Diabetes Mellitus. As a result of this research, we suggest that metformin, either alone or in conjunction with donepezil, might be an excellent drug of choice for neuro-regeneration and risk reduction in Alzheimer\u2019s like disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0271138","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T17:51:17Z","timestamp":1657302677000},"page":"e0271138","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Effects of antidiabetic agents on Alzheimer\u2019s disease biomarkers in experimentally induced hyperglycemic rat model by streptozocin"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7958-9414","authenticated-orcid":true,"given":"Shatw Khalid","family":"Ali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4512-6099","authenticated-orcid":true,"given":"Rojgar H.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"issue":"3","key":"pone.0271138.ref001","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1177\/0891988706291079","article-title":"Alzheimer\u2019s disease and the aging brain","volume":"19","author":"RD Terry","year":"2006","journal-title":"Journal of geriatric psychiatry and neurology"},{"issue":"6","key":"pone.0271138.ref002","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0165-6147(02)02037-0","article-title":"Does insulin dysfunction play a role in Alzheimer\u2019s disease?","volume":"23","author":"L Gasparini","year":"2002","journal-title":"Trends in pharmacological sciences"},{"issue":"4","key":"pone.0271138.ref003","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s007020050068","article-title":"Brain insulin and insulin receptors in aging and sporadic Alzheimer\u2019s disease","volume":"105","author":"L Fr\u00f6lich","year":"1998","journal-title":"Journal of neural transmission"},{"issue":"1","key":"pone.0271138.ref004","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3233\/JAD-2005-7107","article-title":"Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer\u2019s disease\u2013is this type 3 diabetes","volume":"7","author":"E Steen","year":"2005","journal-title":"Journal of Alzheimer\u2019s disease"},{"issue":"2","key":"pone.0271138.ref005","doi-asserted-by":"crossref","first-page":"147","DOI":"10.2174\/156720507780362137","article-title":"Insulin resistance and Alzheimer\u2019s disease pathogenesis: potential mechanisms and implications for treatment","volume":"4","author":"S. 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