背景:我们先前已经证明,氧化应激和脑线粒体功能障碍是心肌梗死(MI)期间脑病理的关键介质。
目的:探讨线粒体动态调节剂的有益作用,包括线粒体裂变抑制剂(Mdivi-1)和线粒体融合启动子(M1),依那普利对MI大鼠认知功能和脑内分子信号传导的影响。
方法:将雄性大鼠分配到假手术或MI手术。在MI组中,包括射血分数小于50%的大鼠,然后他们接受了以下一种治疗5周:车辆,依那普利,Mdivi-1或M1。认知功能进行了测试,大脑被用于分子研究。
结果:MI大鼠表现出全身氧化应激的心功能不全。在MI大鼠中发现认知障碍,随着树突状脊柱的损失,血脑屏障(BBB)破坏,脑线粒体功能障碍,线粒体减少,糖酵解代谢增加,无需修改APP,BACE-1、Tau和p-Tau蛋白。Mdivi-1,M1和依那普利的治疗同样改善了MI大鼠的认知功能。所有治疗都减少了树突状脊柱的损失,脑线粒体氧化应激,并恢复了线粒体代谢.仅在Mdivi-1治疗组中恢复了脑线粒体融合。
结论:线粒体动力学调节剂通过减轻全身氧化应激和脑线粒体功能障碍以及增强线粒体代谢来改善MI大鼠的认知功能。此外,这种线粒体裂变抑制剂增加了MI大鼠的线粒体融合。
BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI).
OBJECTIVE: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of
enalapril.
METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle,
enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study.
RESULTS: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and
enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group.
CONCLUSIONS: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.