Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
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DOI：
10.14336/ad.2019.0120
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发表时间：
2019-10-01
影响因子：
7.4
通讯作者：
Yang, Shao-Hua
中科院分区：
文献类型：
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作者：
Li, Wenjun;Chaudhari, Kiran;Yang, Shao-Hua
二甲双胍是目前治疗2型糖尿病最有效的药物。二甲双胍的有益作用已经被发现，甚至超出了糖尿病的治疗范围，它被认为是最有希望延缓衰老的药物之一。令人惊讶的是，二甲双胍对大脑功能和代谢的影响很少被探索，因为大脑几乎完全使用葡萄糖作为能量代谢的底物。我们测定了二甲双胍对正常血糖小鼠运动和认知功能的影响。二甲双胍可增强运动和平衡能力，但慢性治疗会引起抗焦虑作用和认知功能受损。我们通过体外实验和小鼠代谢组学分析来评估二甲双胍对脑代谢的作用。二甲双胍降低小鼠海马组织ATP水平，激活AMPK通路。二甲双胍在体外治疗剂量下通过抑制线粒体甘油-3-磷酸脱氢酶（mGPDH）抑制氧化磷酸化和糖酵解升高。总之，我们的研究表明，慢性二甲双胍治疗会影响非糖尿病小鼠的脑生物能量学，并对运动和认知脑功能产生复合影响。
Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin's action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.