| First Author | Zang M | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1866 |
| Issue | 11 | Pages | 165890 |
| PubMed ID | 32599143 | Mgi Jnum | J:301678 |
| Mgi Id | MGI:6504161 | Doi | 10.1016/j.bbadis.2020.165890 |
| Citation | Zang M, et al. (2020) The circadian nuclear receptor RORalpha negatively regulates cerebral ischemia-reperfusion injury and mediates the neuroprotective effects of melatonin. Biochim Biophys Acta Mol Basis Dis 1866(11):165890 |
| abstractText | Disruptions of the circadian rhythm and reduced circulating levels of the circadian hormone melatonin predispose to ischemic stroke. Although the nuclear receptor RORalpha 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 RORalpha-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 RORalpha versus non-transgenic controls exerted significantly reduced infarct volume, brain edema and apoptotic response induced by CI/R. Mechanistically, RORalpha 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 RORalpha deficiency intensified the activation of nuclear factor-kappaB signaling induced by CI/R. Given the emerging evidence of RORalpha as an essential melatonin activity mediator, we further investigated the RORalpha 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-kappaB activation, which was eradicated in RORalpha-deficient mice. Collectively, current findings suggest that RORalpha is a novel endogenous neuroprotective receptor, and a pivotal mediator of melatonin's suppressive effects against CI/R injury. |
