UNASSIGNED: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
UNASSIGNED: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes.
UNASSIGNED: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.
■我们进行了大脑中动脉闭塞和氧-葡萄糖剥夺模型,以模拟体内和体外的缺血性中风,分别。使用寡霉素和meclizine触发UPRmt。我们用氯化2,3,5-三苯基四唑染色,行为测试,和Nissl染色以评估体内脑损伤。进行细胞计数试剂盒-8测定和钙黄绿素AM测定试剂盒以在体外测试脑损伤。
■用寡霉素诱导UPRmt保护神经元培养物免受氧-葡萄糖剥夺。UPRmt也可以用meclizine触发,这种食品和药物管理局批准的药物也可以保护神经元免受氧糖剥夺。用针对激活转录因子5的siRNA阻断UPRmt消除了meclizine的神经保护作用。在小鼠局灶性脑缺血模型中,用meclizine预处理能够在体内诱导UPRmt,减少梗塞并改善神经系统预后。
■这些发现表明,UPRmt在维持面临缺血/缺氧应激的神经元的存活方面很重要。UPRmt机制可能为缺血性卒中提供新的治疗途径。