Garg Geetika, Singh Sandeep, Singh Abhishek Kumar, Rizvi Syed Ibrahim
Department of Biochemistry, University of Allahabad , Allahabad, India .
Rejuvenation Res. 2017 Jun;20(3):173-182. doi: 10.1089/rej.2016.1883. Epub 2017 Jan 9.
Metformin, a biguanide, is a widely used antidiabetic drug, which inhibits gluconeogenesis and is used to treat hyperglycemia in type 2 diabetes. Through activation of AMPK (AMP-activated protein kinase) pathway, metformin also mimics caloric restriction health benefits. Aging causes substantial molecular to morphological changes in brain, the brain cells being more susceptible toward oxidative stress mediated damages due to the presence of high lipid content and higher oxygen consumption. Wistar rats (naturally aged and d-galactose induced rat model) were supplemented with metformin (300 mg/kg b.w. orally) for 6 weeks. The biomarkers of oxidative stress such as antioxidant capacity (ferric reducing antioxidant potential [FRAP]), malondialdehyde (MDA), reduced glutathione (GSH), protein carbonyl (PCO), reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, and nitric oxide (NO) were measured in brain tissues of control and experimental groups. The results indicate that metformin treatment augmented the levels of FRAP and GSH in naturally aged, and d-gal induced aging model groups compared to the respective controls. In contrast, metformin treated groups exhibited significant reduction in MDA, PCO, ROS, and NO levels and a significant increase in AChE activity in induced aging rats. The administration of d-galactose upregulated the expression of sirtuin-2, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and downregulated the expression of Beclin-1. Metformin supplementation downregulated the d-galactose induced expressions of sirtuin-2, IL-6, and TNF-α expression, whereas upregulated the Beclin-1 expression. Our data confirm that metformin restores the antioxidant status and improves healthy brain aging through the activation of autophagy and reduction in inflammation.
二甲双胍是一种双胍类药物，是一种广泛使用的抗糖尿病药物，它可抑制糖异生，用于治疗2型糖尿病的高血糖症。通过激活AMPK（AMP激活的蛋白激酶）途径，二甲双胍还能模拟热量限制对健康的益处。衰老会导致大脑发生从分子到形态的显著变化，由于大脑细胞中脂质含量高且氧消耗量大，它们更容易受到氧化应激介导的损伤。给Wistar大鼠（自然衰老和d-半乳糖诱导的大鼠模型）口服补充二甲双胍（300mg/kg体重），持续6周。在对照组和实验组的脑组织中测量了氧化应激的生物标志物，如抗氧化能力（铁还原抗氧化能力[FRAP]）、丙二醛（MDA）、还原型谷胱甘肽（GSH）、蛋白质羰基（PCO）、活性氧（ROS）、乙酰胆碱酯酶（AChE）活性和一氧化氮（NO）。结果表明，与各自的对照组相比，二甲双胍治疗可提高自然衰老组和d-半乳糖诱导的衰老模型组中FRAP和GSH的水平。相反，在诱导衰老的大鼠中，二甲双胍治疗组的MDA、PCO、ROS和NO水平显著降低，AChE活性显著增加。给予d-半乳糖会上调沉默调节蛋白2、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）的表达，并下调Beclin-1的表达。补充二甲双胍可下调d-半乳糖诱导的沉默调节蛋白2、IL-6和TNF-α的表达，而上调Beclin-1的表达。我们的数据证实，二甲双胍通过激活自噬和减轻炎症来恢复抗氧化状态并改善大脑健康衰老。
