Department of Neural and Behavioral Sciences, H109, College of Medicine, Hershey Medical Center, Penn State College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA, 17033, USA.
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Penn State University, Hershey, PA, USA.
Pharmacol Rep. 2022 Aug;74(4):696-708. doi: 10.1007/s43440-022-00382-z. Epub 2022 Jul 6.
Diabetes is an independent risk factor of stroke and previous studies have confirmed that diabetic patients and animals experience poorer clinical outcomes following stroke. In this study, we aim to determine the effect of chronic exposure of the first-line antidiabetic agent, metformin, to restore euglycemia and to impact brain cell death following stroke in a new type-2 diabetes, NONcNZO10/LtJ (RCS-10) mouse model of stroke.
Male RCS-10 mice received a moderate (11%) fat diet post-weaning, at 4 weeks of age, and became diabetic by 12-14 weeks, thus resembling human maturity-onset diabetes. The mice received either metformin or vehicle for 4 weeks before undergoing a hypoxic/ischemic (HI) insult. Blood samples were collected pre-, post-treatment, and post HI for glucose and lipid measurements, and brains were analyzed for infarct size, glial activation, neuronal cell death, and metformin-mediated adenosine monophosphate-activated protein kinase (AMPK) signaling at 48 h post HI.
Pretreatment with metformin maintained euglycemia for 4 weeks but did not change body weight or lipid profile. Metformin treatment significantly enhanced the microglial Bfl-1 mRNA expression and showed a non-significant increase in GFAP mRNA, however, GFAP protein levels were reduced. Metformin treatment slightly increased neuronal NeuN and MAP-2 protein levels and significantly reduced overall mortality post HI but did not elicit any significant change in infarct size.
The study suggests that the prolonged effect of metformin-induced euglycemia promoted the microglial activation, reduced neuronal cell death, and improved the overall survival following stroke, without any change in infarct size.
糖尿病是中风的一个独立危险因素，既往研究已证实，糖尿病患者和动物中风后临床预后较差。在本研究中，我们旨在确定一线抗糖尿病药物二甲双胍的慢性暴露，恢复血糖正常，并对新型 2 型糖尿病 NONcNZO10/LtJ（RCS-10）中风小鼠模型中风后脑细胞死亡的影响。
雄性 RCS-10 小鼠在 4 周龄时接受高（11%）脂肪饮食，12-14 周时发生糖尿病，从而类似于人类成年发病型糖尿病。在接受缺氧/缺血（HI）损伤前，小鼠接受二甲双胍或载体治疗 4 周。在治疗前、治疗后和 HI 后采集血样，用于血糖和血脂检测，并在 HI 后 48 小时分析脑梗死面积、胶质细胞激活、神经元细胞死亡和二甲双胍介导的 AMP 激活蛋白激酶（AMPK）信号。
二甲双胍预处理可维持血糖正常 4 周，但不改变体重或血脂谱。二甲双胍治疗显著增强了小胶质细胞 Bfl-1mRNA 的表达，并显示出 GFAPmRNA 的非显著性增加，但 GFAP 蛋白水平降低。二甲双胍治疗轻度增加神经元 NeuN 和 MAP-2 蛋白水平，并显著降低 HI 后总死亡率，但对梗死面积无任何显著影响。
该研究表明，二甲双胍诱导的血糖正常的长期作用促进了中风后小胶质细胞的激活，减少了神经元细胞死亡，并提高了整体生存率，而对梗死面积没有任何影响。
