Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1‐dependent mechanism during ischemic‐stroke in mice

Abstract

Silent information regulator 1 (SIRT1), a type of histone deacetylase, is a highly effective therapeutic target for protection against ischemia reperfusion (IR) injury (IRI). Previous studies showed that melatonin preserves SIRT1 expression in neuronal cells of newborn rats after hypoxia-ischemia. However, the definite role of SIRT1 in the protective effect of melatonin against cerebral IRI in adult has not been explored. In this study, the brain of adult mice was subjected to IRI. Prior to this procedure, the mice were given intraperitoneal with or without the SIRT1 inhibitor, EX527. Melatonin conferred a cerebral-protective effect, as shown by reduced infarct volume, lowered brain edema, and increased neurological scores. The melatonin-induced upregulation of SIRT1 was also associated with an increase in the anti-apoptotic factor, Bcl2, and a reduction in the pro-apoptotic factor Bax. Moreover, melatonin resulted in a well-preserved mitochondrial membrane potential, mitochondrial Complex I activity, and mitochondrial cytochrome c level while it reduced cytosolic cytochrome c level. However, the melatonin-elevated mitochondrial function was reversed by EX527 treatment. In summary, our results demonstrate that melatonin treatment attenuates cerebral IRI by reducing IR-induced mitochondrial dysfunction through the activation of SIRT1 signaling.

Kaempferol protects cardiomyocytes against anoxia/reoxygenation injury via mitochondrial pathway mediated by SIRT1

“…All these findings suggested that the cardioprotective effect of Kae in cardiomyocytes subjected to A/R was related to mitochondrial pathway. The latest research shows that melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice (Yang et al, 2015).…”

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

“…There were a few studies on the systemic administration of EX527 to mice, 44,45 and no adverse effect of EX527 was noted. Among the other inhibitors of SIRT1 and 2, an intravenous injection (twice a week for 4 weeks) of sirtinol (10 mg/kg) and a daily intraperitoneal injection of cambinol (100 mg/kg) did not induce weight loss or adverse effects.…”

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…Melatonin confered cardioprotective effect against myocardial ischemia reperfusion injury by reducing oxidative stress damage via activation of SIRT1 signaling in a receptor-dependent manner . Melatonin treatment also attenuated cerebral ischemia-reperfusion injury in mice by reducing ischemia reperfusion-induced mitochondrial dysfunction through the activation of SIRT1 signaling and the attenuation of mitochondrial oxidative damage (Yang et al, 2015).…”