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. 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.
Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, China.
Yang
Y
Yang
Shuai
S
Jiang
Yushu
Y
Dong
Chongxi
C
Fan
Lei
L
Zhao
Xiangmin
X
Yang
Juan
J
Li
Shouyin
S
Di
Liang
L
Yue
Guobiao
G
Liang
Russel J
RJ
Reiter
Yan
Y
Qu
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000975:Antioxidants; D002227:Carbazoles; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008550:Melatonin
SIRT1 signaling; cerebral-protection; ischemia reperfusion; melatonin; mitochondrial dysfunction