Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; 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 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.
Eur J Pharmacol. 2023 Oct 5;956:175939. doi: 10.1016/j.ejphar.2023.175939. Epub 2023 Aug 1.
An imbalance of brain mitochondrial dynamics, increases in brain inflammation and apoptosis, and increasing cognitive dysfunction, have been reported as being associated with prediabetes and myocardial ischemia-reperfusion (IR) injury. Since inhibiting mitochondrial fission with Mdivi-1 or promoting fusion with M1 had cardioprotective effects in myocardial IR injury and obesity, the neuroprotective roles of Mdivi-1 and M1 when administered at different time points of myocardial IR injury in obese prediabetes have never been determined. Ninety-six male Wistar rats were fed with either a normal (ND: n = 8) or a high-fat diet to induce prediabetes (HFD: n = 88) for 12 weeks. At week 13, all rats were subjected to left anterior descending coronary artery ligation for 30 min, followed by reperfusion for 120 min. HFD rats were randomly divided into 10 groups and assigned into either a pre-ischemic group treated with vehicle (HFV), pre-ischemic, during-ischemic, or onset of reperfusion groups treated with either Mdivi-1 (MDV), M1, or combined (COM). Heart function was examined invasively, with the heart being terminated to investigate myocardial infarction. Brains were collected to determine mitochondrial functions, inflammation, apoptosis, and pathological markers. Mdivi-1, M1, and COM treatment at different periods exerted cardioprotection against myocardial IR injury in HFD-fed rats by reducing infarct size and left ventricular dysfunction. All interventions also improved all brain pathologies against myocardial IR injury in prediabetic rats. These findings suggest that differential temporal modulation of mitochondrial dynamics may be appropriate regimens for preventing heart and brain complications after myocardial IR injury in obese prediabetes.
脑线粒体动力学失衡、脑炎症和细胞凋亡增加以及认知功能障碍增加已被报道与糖尿病前期和心肌缺血再灌注（IR）损伤有关。由于用 Mdivi-1 抑制线粒体裂变或用 M1 促进融合在心肌 IR 损伤和肥胖症中具有心脏保护作用，因此从未确定过 Mdivi-1 和 M1 在肥胖糖尿病前期心肌 IR 损伤的不同时间点给药时的神经保护作用。96 只雄性 Wistar 大鼠分别喂食正常饮食（ND：n=8）或高脂肪饮食（HFD：n=88）12 周以诱导糖尿病前期。在第 13 周，所有大鼠均进行左前降支冠状动脉结扎 30 分钟，然后再灌注 120 分钟。HFD 大鼠随机分为 10 组，分为缺血前组给予载体（HFV）、缺血前、缺血期间或再灌注开始时给予 Mdivi-1（MDV）、M1 或联合（COM）治疗组。通过侵入性检查心功能，终止心脏以研究心肌梗死。收集大脑以确定线粒体功能、炎症、细胞凋亡和病理标志物。Mdivi-1、M1 和 COM 在不同时期的治疗对 HFD 喂养大鼠的心肌 IR 损伤具有心脏保护作用，减少梗死面积和左心室功能障碍。所有干预措施也改善了糖尿病前期大鼠心肌 IR 损伤后的所有大脑病理学变化。这些发现表明，线粒体动力学的差异时间调节可能是预防肥胖糖尿病前期心肌 IR 损伤后心脏和大脑并发症的适当方案。
