SIRT2/HSF1/PERK pathway is essential for melatonin-alleviated endoplasmic reticulum stress in cerebral ischemic/reperfusion injury

Abstract Background: Targeting endoplasmic reticulum (ER) stress with melatonin has been proven helpful for cerebral ischemic/reperfusion (CI/R) damage, while the mechanism remains unclear. In current study, we investigated whether melatonin could ameliorate ER stress in CI/R injury through sirtuin 2 (SIRT2). Methods: Male SD rats were underwent middle cerebral artery occlusion and reperfusion (MCAO-R) surgery. Melatonin was treated 30 min before MCAO-R. Results: Melatonin (20 mg/kg) notably improved MCAO-R-induced cerebral neurologic impairment and infarct volume. Melatonin reversed MCAO-R induced upregulation of SIRT2 and activation of ER stress (reduced phosphorylated protein kinase-like ER kinase (PERK) and phosphorylated eukaryotic initiation factor 2α). Consistently, in OGD/R-treated HT22 cells, melatonin also significantly alleviated ER stress and SIRT2 expression. Further Co-immunoprecipitation and co-immunofluorescence studies revealed that melatonin enhanced heat shock factor 1 (HSF 1)acetylation. Inhibiting of Sirt2 by siRNA also increased HSF1 acetylation in OGD/R-treated cells. Melatonin significantly inhibited PERK activator (CCT020312)-induced ER stress, while CCT020312 had no influence on SIRT2 and HSF1 acetylation. Conclusion: Our findings elucidated that SIRT2/HSF1/PERK pathway is essential for melatonin-alleviated CI/R injury, providing a novel molecular mechanism.