Obafemi Tajudeen Olabisi, Olasehinde Oluwaseun R, Olaoye Oyindamola A, Jaiyesimi Kikelomo F, Adewumi Funmilayo D, Adewale Olusola B, Afolabi Blessing A
Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454 Nigeria.
Medical Biochemistry Unit, College of Health Sciences, Afe Babalola University, PMB 5454, Ado-Ekiti, Nigeria.
J Diabetes Metab Disord. 2020 May 16;19(1):499-510. doi: 10.1007/s40200-020-00541-0. eCollection 2020 Jun.
Diabetes mellitus is associated with perturbations in brain biochemical parameters associated with dementia. This study aimed at comparing the effect of metformin and metformin/donepezil combination on oxidative stress, endoplasmic reticulum stress and inflammation in the brain of diabetic Wistar rats.
Diabetes was induced by single intraperitoneal injection of 40 mg/kg streptozotocin after administration of 10% fructose for 14 days. Animals were randomly assigned to four groups of five animals each. Group 1 was the normal control and received only distilled water. Groups 2 and 3 were diabetic rats treated with metformin/donepezil combination and metformin only respectively, while group 4 was diabetic control. Treatment lasted for 21 days after confirmation of diabetes. Activities of acetylcholinesterase (AchE), butyrylcholinesterase (BchE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase were evaluated in the brain of diabetic rats. Enzyme-linked immunosorbent assay was used to estimate brain levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) malondialdehyde and glucose transporter-4 (GLUT4), while expression of endoplasmic reticulum stress markers - glucose regulated protein-78 (GRP78), activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) was determined using real-time PCR in the hippocampus of diabetic rats.
Treatment with metformin/donepezil combination significantly reduced the activities of AchE, BchE as well as levels of malondialdehyde, TNF-α and IL-6, while the activities of SOD, GPx and catalase were significantly increased in the brain. Moreover, expression of ER stress markers was attenuated in the hippocampus.
Metformin/donepezil combination appeared more efficacious than metformin only and could be considered for managing diabetes-associated dementia.
糖尿病与痴呆相关的脑生化参数紊乱有关。本研究旨在比较二甲双胍和二甲双胍/多奈哌齐联合用药对糖尿病Wistar大鼠脑内氧化应激、内质网应激和炎症的影响。
在给予10%果糖14天后，通过单次腹腔注射40mg/kg链脲佐菌素诱导糖尿病。将动物随机分为四组，每组五只。第1组为正常对照组，仅接受蒸馏水。第2组和第3组分别为用二甲双胍/多奈哌齐联合用药和仅用二甲双胍治疗的糖尿病大鼠，而第4组为糖尿病对照组。在确诊糖尿病后治疗持续21天。评估糖尿病大鼠脑内乙酰胆碱酯酶（AchE）、丁酰胆碱酯酶（BchE）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和过氧化氢酶的活性。采用酶联免疫吸附测定法估计脑内肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、丙二醛和葡萄糖转运蛋白4（GLUT4）的水平，同时使用实时PCR测定糖尿病大鼠海马体内质网应激标志物——葡萄糖调节蛋白78（GRP78）、激活转录因子4（ATF4）和C/EBP同源蛋白（CHOP）的表达。
二甲双胍/多奈哌齐联合用药显著降低了AchE、BchE的活性以及丙二醛、TNF-α和IL-6的水平，同时脑内SOD、GPx和过氧化氢酶的活性显著增加。此外，海马体内质网应激标志物的表达减弱。
二甲双胍/多奈哌齐联合用药似乎比单用二甲双胍更有效，可考虑用于治疗糖尿病相关痴呆。
