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

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. H...

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Bibliographic Details
Published in:Journal of pineal research 2015-01, Vol.58 (1), p.61-70
Main Authors: Yang, Yang, Jiang, Shuai, Dong, Yushu, Fan, Chongxi, Zhao, Lei, Yang, Xiangmin, Li, Juan, Di, Shouyin, Yue, Liang, Liang, Guobiao, Reiter, Russel J., Qu, Yan
Format: Article
Language:English
Subjects:
Animals
Antioxidants - pharmacology
Brain Ischemia - drug therapy
Brain Ischemia - metabolism
Brain Ischemia - pathology
Carbazoles - pharmacology
Cell Death - drug effects
cerebral-protection
ischemia reperfusion
Male
melatonin
Melatonin - pharmacology
Mice
Mitochondria - metabolism
Mitochondria - pathology
mitochondrial dysfunction
Rats
Signal Transduction - drug effects
SIRT1 signaling
Sirtuin 1 - antagonists & inhibitors
Sirtuin 1 - metabolism
Stroke - drug therapy
Stroke - metabolism
Stroke - pathology
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Summary: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.
ISSN:0742-3098
1600-079X
DOI:10.1111/jpi.12193