Disruptions of the circadian rhythm and reduced circulating levels of the circadian hormone melatonin predispose to ischemic stroke. Although the nuclear receptor RORα is considered as a circadian rhythm regulator and a mediator of certain melatonin effects, its potential role in cerebral ischemia-reperfusion (CI/R) injury and in the neuroprotective effects of melatonin remain undefined. Here, we observed that CI/R injury in RORα-deficient mice was associated with greater cerebral infarct size, brain edema, and cerebral apoptosis compared with wild-type model. In contrast, transgenic mice with brain-specific overexpression of RORα versus non-transgenic controls exerted significantly reduced infarct volume, brain edema and apoptotic response induced by CI/R. Mechanistically, RORα deficiency was found to exacerbate apoptosis pathways mediated by endoplasmic-reticulum stress and mitochondria and aggravate oxidative/nitrative stress after CI/R. Further studies revealed that RORα deficiency intensified the activation of nuclear factor-κB signaling induced by CI/R. Given the emerging evidence of RORα as an essential melatonin activity mediator, we further investigated the RORα roles in melatonin-exerted neuroprotection against acute ischemic stroke. Melatonin treatment significantly decreased infarct volume and cerebral apoptosis; mitigated endoplasmic reticulum stress and mitochondrial dysfunction; and inhibited CI/R injury-induced oxidative/nitrative stress and nuclear factor-κB activation, which was eradicated in RORα-deficient mice. Collectively, current findings suggest that RORα is a novel endogenous neuroprotective receptor, and a pivotal mediator of melatonin's suppressive effects against CI/R injury.

昼夜节律的破坏和昼夜节律激素褪黑激素的循环水平降低易患缺血性中风。尽管核受体RORα被认为是昼夜节律的调节器和某些褪黑激素作用的介体，但其在脑缺血再灌注（CI / R）损伤和褪黑激素的神经保护作用中的潜在作用仍然不确定。在这里，我们观察到与野生型模型相比，RORα缺陷型小鼠的CI / R损伤与更大的脑梗死面积，脑水肿和脑细胞凋亡相关。相反，与非转基因对照相比，具有RORα的脑特异性过表达的转基因小鼠的CI / R诱导的梗塞面积，脑水肿和凋亡反应明显降低。机械上，RORα缺乏被发现加剧了内质网应激和线粒体介导的凋亡通路，并加剧了CI / R后的氧化/硝化应激。进一步的研究表明，RORα缺乏增强了CI / R诱导的核因子-κB信号的激活。鉴于RORα作为必需的褪黑激素活性介体的新兴证据，我们进一步研究了RORα在褪黑素对急性缺血性中风的神经保护中的作用。褪黑素治疗可显着减少梗死体积和脑细胞凋亡；减轻内质网应激和线粒体功能障碍；并抑制CI / R损伤诱导的氧化/硝化应激和核因子-κB活化，这已在RORα缺陷型小鼠中消除。总的来说，