Department of Anesthesiology, Lamphun Hospital, Lamphun, Thailand.
Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
J Alzheimers Dis. 2020;77(3):993-1003. doi: 10.3233/JAD-200495.
Cardiac ischemia/reperfusion (I/R) injury induces brain damage through increased blood-brain barrier (BBB) breakdown, microglial hyperactivity, pro-inflammatory cytokines, amyloid-β deposition, loss of dendritic spines, brain mitochondrial dysfunction, and imbalanced mitochondrial dynamics. Previous studies demonstrated that mitochondrial fusion promoter reduced cardiac damage from cardiac I/R injury; however, following cardiac I/R injury, the roles of mitochondrial dynamics on the brain have not been investigated.
To investigate the effects of pharmacological modulation using mitochondrial fusion promoter (M1) in the brain of rats following cardiac I/R injury.
Twenty-four male Wistar rats were separated into two groups; 1) sham-operation (n = 8) and 2) cardiac I/R injury (n = 16). Rats in the cardiac I/R injury group were randomly received either normal saline solution as a vehicle or a mitochondrial fusion promoter (M1, 2 mg/kg) intravenously. Both treatments were given to the rats 15 minutes before cardiac I/R injury. At the end of the reperfusion protocol, the brain was rapidly removed to investigate brain mitochondrial function, mitochondrial dynamics proteins, microglial activity, and Alzheimer's disease (AD) related proteins.
Cardiac I/R injury induced brain mitochondrial dynamics imbalance as indicated by reduced mitochondrial fusion proteins expression without alteration in mitochondrial fission, brain mitochondrial dysfunction, BBB breakdown, increased macrophage infiltration, apoptosis, and AD-related proteins. Pretreatment with M1 effectively increased the expression of mitofusin 2, a mitochondrial outer membrane fusion protein, reduced brain mitochondrial dysfunction, BBB breakdown, macrophage infiltration, apoptosis, and AD-related proteins in rats following cardiac I/R injury.
This mitochondrial fusion promoter significantly protected rats with cardiac I/R injury against brain damage.
心脏缺血/再灌注（I/R）损伤通过增加血脑屏障（BBB）破裂、小胶质细胞过度活跃、促炎细胞因子、淀粉样β沉积、树突棘丧失、脑线粒体功能障碍和线粒体动力学失衡导致脑损伤。先前的研究表明，线粒体融合促进剂可减轻心脏 I/R 损伤引起的心脏损伤；然而，心脏 I/R 损伤后，线粒体动力学对大脑的作用尚未得到研究。
研究心脏 I/R 损伤后使用线粒体融合促进剂（M1）对大鼠大脑的影响。
将 24 只雄性 Wistar 大鼠分为两组；1）假手术（n=8）和 2）心脏 I/R 损伤（n=16）。心脏 I/R 损伤组的大鼠随机接受生理盐水溶液作为载体或线粒体融合促进剂（M1，2mg/kg）静脉注射。两种治疗方法均在心脏 I/R 损伤前 15 分钟给予大鼠。再灌注方案结束时，迅速取出大脑以研究脑线粒体功能、线粒体动力学蛋白、小胶质细胞活性和阿尔茨海默病（AD）相关蛋白。
心脏 I/R 损伤诱导脑线粒体动力学失衡，表现为线粒体融合蛋白表达减少，而线粒体分裂无变化，脑线粒体功能障碍，BBB 破裂，巨噬细胞浸润增加，细胞凋亡和 AD 相关蛋白增加。M1 预处理可有效增加线粒体融合蛋白（mitofusin 2）的表达，减少心脏 I/R 损伤大鼠的脑线粒体功能障碍、BBB 破裂、巨噬细胞浸润、细胞凋亡和 AD 相关蛋白。
这种线粒体融合促进剂可显著保护心脏 I/R 损伤大鼠免受脑损伤。
