Apelin-36 Protects HT22 Cells Against Oxygen-Glucose Deprivation/Reperfusion-Induced Oxidative Stress and Mitochondrial Dysfunction by Promoting SIRT1-Mediated PINK1/Parkin-Dependent Mitophagy

NEUROTOXICITY RESEARCH(2021)

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摘要
Oxidative stress and mitochondrial dysfunction are involved in cerebral ischemia/reperfusion injury-induced neuronal apoptosis. Mitophagy is the main method to eliminate dysfunctional mitochondria. Apelin-36, a type of neuropeptide, has been reported to exert protective effects in cerebral I/R (I/R) injury, but its precise mechanisms remain to be elucidated. To study the effects of Apelin-36 on oxidative stress and mitochondrial dysfunction in cerebral I/R injury, the oxygen-glucose deprivation/reperfusion (OGD/R) model with 6 h of ischemia and 6 h of reperfusion was established in HT22 cells. Results demonstrated that Apelin-36 protected against OGD/R injury by improving cell viability, decreasing the apoptotic cells ratio and increasing the ratio of Bcl-2/Bax. In addition, Apelin-36 treatment inhibited oxidative stress by downregulating the level of reactive oxygen species (ROS) and malondialdehyde (MDA) as well as the expression of inducible nitric oxide synthase (iNOS). And Apelin-36 also activated the level of superoxide dismutase (SOD) and glutathione (GSH). Mitochondrial apoptosis was also alleviated with Apelin-36 treatment detected by the mitochondrial membrane potential (MMP) and the expression of Cytochrome c (Cyt c ), Cleaved caspase-9, and Cleaved caspase-3. Furthermore, the SIRT1-mediated PINK1/Parkin-dependent mitophagy was activated by Apelin-36 treatment with the downregulation of p62 and upregulation of LC3B-II and Beclin1. Both EX527 and Cyclosporine A (CsA), which are inhibitors of SIRT1 and mitophagy, markedly alleviated the inhibition of oxidative stress and mitochondrial dysfunction caused by Apelin-36. These findings suggest that SIRT1-mediated PINK1/Parkin-dependent mitophagy is involved in the neuroprotective effects of Apelin-36 on OGD/R-induced oxidative stress and mitochondrial dysfunction.
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关键词
Apelin-36, Oxidative stress, Mitochondrial&#160, dysfunction, Mitophagy, Oxygen-glucose deprivation, reperfusion injury
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