Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Eur J Pharmacol. 2020 Oct 15;885:173418. doi: 10.1016/j.ejphar.2020.173418. Epub 2020 Aug 2.
Myocardial ischemia is the malperfusion of cardiac tissue due to a blockage in a coronary artery. Subsequent return of blood flow to the ischemic area of the heart, results in ischemia/reperfusion (I/R) injury in the heart and other organs, including the brain. Besides the cardioprotective effects of metformin on the heart against cardiac I/R injury, metformin also reduced neuronal injury in a stroke model. However, the effects of metformin on the brain following cardiac I/R injury has not yet been investigated. Therefore, we hypothesize that metformin reduces brain damage via decreasing brain mitochondrial dysfunction, microglial hyperactivity, and Alzheimer's proteins in rats after cardiac I/R injury. Rats (n = 50) received either a sham operation (n = 10) or cardiac I/R (n = 40). Cardiac I/R was induced by 30 min of cardiac ischemia, followed by 120 min of reperfusion. Rats in cardiac I/R group were divided into 4 groups (n = 10/group); vehicle, metformin 100 mg/kg, metformin 200 mg/kg, and metformin 400 mg/kg. Metformin was given via femoral vein at 15 min prior to cardiac ischemia. At the end of reperfusion, brains were removed to determine dendritic spine density, brain mitochondrial function, microglial morphology, and amyloid beta formation. Cardiac I/R injury led to brain mitochondrial dysfunction, microglial hyperactivation, amyloid beta formation, Tau hyperphosphorylation, and reduced dendritic spine density with an increase in AMPK activation. All doses of metformin improved brain pathologies in rats with cardiac I/R injury possibly via activating cerebral AMPK. In summary, pre-treatment with metformin offers neuroprotection against the brain damages caused by cardiac I/R injury.
心肌缺血是由于冠状动脉阻塞导致的心肌组织灌注不足。随后，血液回流到心脏缺血区域，导致心脏和其他器官（包括大脑）发生缺血/再灌注（I/R）损伤。除了二甲双胍对心脏 I/R 损伤的心脏保护作用外，二甲双胍还可减轻中风模型中的神经元损伤。然而，二甲双胍对心脏 I/R 损伤后大脑的影响尚未得到研究。因此，我们假设二甲双胍通过降低大脑线粒体功能障碍、小胶质细胞过度活跃和阿尔茨海默病蛋白来减少心脏 I/R 损伤后大鼠的脑损伤。将大鼠（n=50）分为假手术组（n=10）或心脏 I/R 组（n=40）。通过 30 分钟的心肌缺血诱导心脏 I/R，随后再灌注 120 分钟。心脏 I/R 组的大鼠再分为 4 组（n=10/组）：载体、二甲双胍 100mg/kg、二甲双胍 200mg/kg 和二甲双胍 400mg/kg。在心肌缺血前 15 分钟通过股静脉给予二甲双胍。再灌注结束时，取出大脑以确定树突棘密度、大脑线粒体功能、小胶质细胞形态和淀粉样β形成。心脏 I/R 损伤导致大脑线粒体功能障碍、小胶质细胞过度活跃、淀粉样β形成、Tau 过度磷酸化和树突棘密度降低，同时 AMPK 激活增加。所有剂量的二甲双胍均可改善心脏 I/R 损伤大鼠的大脑病理，可能是通过激活大脑 AMPK。总之，心脏 I/R 损伤前用二甲双胍预处理可提供脑保护作用，防止大脑损伤。
