Following acute myocardial infarction, re-establishment of coronary perfusion aggravates further injuries in the heart and remote organs including the brain as a consequence of ischemia/reperfusion (I/R) injury. Since pretreatment with metformin attenuated both cardiac and cerebral I/R injury via AMP-activated protein kinase (AMPK) pathways, we hypothesized that metformin given after ischemia mitigates both cardiac and brain pathologies following cardiac I/R. Male Wistar rats were subjected to either cardiac I/R (30 min-ischemia/120 min-reperfusion; n = 30) or sham operation (n = 5). Metformin 200 mg/kg was given intravenously to the cardiac I/R group (n = 10/group), either during ischemia (D-MET) or at the onset of reperfusion (R-MET). Left ventricular ejection fraction (LVEF) and arrhythmia scores were determined. The heart and brain tissues were collected to determine the extent of injury, mitochondrial function, and apoptosis. Additionally, microglial morphology, Alzheimer's proteins, and dendritic spine density were determined in the brain. Cardiac I/R led to not only reduced LVEF, cardiac mitochondrial dysfunction, and arrhythmias, but also brain mitochondrial dysfunction, apoptosis, Alzheimer's protein aggregation, microglial activation, and dendritic spine loss. A single dose of metformin did not alter p-AMPK/AMPK in both organs. In the heart, impaired LVEF, arrhythmias, infarct size expansion, mitochondrial dysfunction, and apoptosis were not alleviated. On the contrary, metformin attenuated brain mitochondrial dysfunction, apoptosis, and Alzheimer's protein levels. Microglial morphology and dendritic spine density were additionally preserved in D-MET group. In conclusion, metformin given during ischemia preferentially provides neuroprotection against brain mitochondrial dysfunction, apoptosis, microglial activation, and dendritic spine loss in an AMPK-independent manner following cardiac I/R injury.

急性心肌梗塞后，由于缺血/再灌注（I / R）损伤，冠状动脉灌注重建会加重心脏和远端器官（包括脑）的进一步伤害。由于二甲双胍预处理通过AMP激活的蛋白激酶（AMPK）途径减轻了心脏和大脑的I / R损伤，因此我们假设缺血后给予的二甲双胍可以减轻心脏I / R后的心脏和大脑病变。对雄性Wistar大鼠进行心脏I / R（缺血30分钟/再灌注120分钟；n  = 30）或假手术（n  = 5）。心脏I / R组静脉注射200 mg / kg的二甲双胍（n = 10 /组），无论是在缺血期间（D-MET）还是在再灌注开始时（R-MET）。确定左心室射血分数（LVEF）和心律不齐评分。收集心脏和脑组织以确定损伤程度，线粒体功能和凋亡。此外，还确定了大脑中的小胶质细胞形态，阿尔茨海默氏病蛋白和树突棘密度。心脏I / R不仅导致LVEF降低，心脏线粒体功能障碍和心律不齐，而且导致脑线粒体功能障碍，凋亡，阿尔茨海默氏症蛋白聚集，小胶质细胞活化和树突棘丧失。单剂量二甲双胍不会改变两个器官中的p-AMPK / AMPK。在心脏中，LVEF受损，心律不齐，梗死面积扩大，线粒体功能障碍和细胞凋亡均未缓解。反之，二甲双胍可减轻脑线粒体功能障碍，细胞凋亡和阿尔茨海默氏症蛋白水平。D-MET组还保留了小胶质细胞形态和树突棘密度。综上所述，在心脏I / R损伤后，缺血期间给予的二甲双胍可以以不依赖AMPK的方式优先提供针对脑线粒体功能障碍，细胞凋亡，小胶质细胞活化和树突棘丧失的神经保护作用。