Department of Pharmacology and Toxicology, Hawler Medical University, Erbil, Iraq.
PLoS One. 2022 Jul 8;17(7):e0271138. doi: 10.1371/journal.pone.0271138. eCollection 2022.
Alzheimer's disease is the most common cause of dementia in the elderly population. It is characterized by the accumulation of amyloid β 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's 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's disease. The aim of this study was to investigate the impact of anti-diabetic agents on Alzheimer's disease progression and the levels of Alzheimer's biomarkers in a hyperglycaemic rat model, which was induced by intraperitoneal injection of streptozocin to produce insulin-deficient diabetes.
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.
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 β 42, total plasma tau, and neurofilament light. A significant increase was also found in brain amyloid β 42, nitric oxide, acetylcholinesterase, malondialdehyde, β secretase, and phosphorylated microtubule-associated protein tau. The greatest statistically significant reductions in serum glucose, haemoglobin A1c, triglycerides, amyloid β 42, total plasma tau, brain amyloid β 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 β 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.
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 β 42, nitric oxide, acetylcholinesterase, malondialdehyde, and β 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's like disease.
阿尔茨海默病是老年人中最常见的痴呆症病因。其特征是大脑中β淀粉样蛋白和神经元内神经原纤维缠结的积累。越来越多的证据表明，大脑中胰岛素信号的紊乱可能导致阿尔茨海默病的病理生理学变化。在 1 型糖尿病中，这些破坏是由低胰岛素血症引起的，但在 2 型糖尿病中，它们是由胰岛素抵抗和胰岛素分泌减少引起的。多项研究表明，糖尿病与阿尔茨海默病风险增加有关。本研究旨在探讨在链脲佐菌素（streptozocin）诱导的高血糖大鼠模型中，抗糖尿病药物对阿尔茨海默病进展和阿尔茨海默病生物标志物水平的影响，该模型通过腹腔注射产生胰岛素缺乏型糖尿病。
将 36 只雄性 Wistar 白化大鼠分为 6 组，每组 6 只。第 I 组为阴性对照组。5 个实验组一次性腹腔注射链脲佐菌素（42mg/kg）。第 II 组为阳性对照组。第 III、IV、V 和 VI 组大鼠分别给予二甲双胍（300mg/kg）、多奈哌齐（10mg/kg）、甘精胰岛素（3 单位/动物）和格列本脲（10mg/kg），共 21 天。
诱导大鼠高血糖显著增加了血清葡萄糖、糖化血红蛋白 A1c、总胆固醇、甘油三酯、高密度脂蛋白、白细胞介素 6、肿瘤坏死因子 α、β淀粉样蛋白 42、总血浆 tau 和神经丝轻链。大脑中β淀粉样蛋白 42、一氧化氮、乙酰胆碱酯酶、丙二醛、β 分泌酶和磷酸化微管相关蛋白 tau 也显著增加。用二甲双胍治疗的大鼠血清葡萄糖、糖化血红蛋白 A1c、甘油三酯、β淀粉样蛋白 42、总血浆 tau、脑β淀粉样蛋白 42、乙酰胆碱酯酶和丙二醛水平降低最显著。相反，用多奈哌齐治疗的大鼠血清肿瘤坏死因子 α、脑一氧化氮和β 分泌酶降低最显著。用甘精胰岛素治疗的大鼠脑中神经丝轻链和磷酸化微管相关蛋白 tau 的水平明显低于其他治疗组。用格列本脲治疗的大鼠总胆固醇和低密度脂蛋白水平下降最显著。
在本研究中，当给予适当剂量时，二甲双胍和多奈哌齐成功降低了大多数血浆和脑生物标志物，包括葡萄糖、甘油三酯、肿瘤坏死因子 α、β 淀粉样蛋白 42、一氧化氮、乙酰胆碱酯酶、丙二醛和β 分泌酶，在患有糖尿病的大鼠中。基于这项研究，我们建议二甲双胍，无论是单独使用还是与多奈哌齐联合使用，都可能是治疗阿尔茨海默病样疾病神经再生和降低风险的一种极好的药物选择。
