期刊
NEUROSCIENCE
卷 366, 期 -, 页码 95-104出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2017.09.035
关键词
cerebral ischemia/reperfusion; oxidative stress; sirtuin 6; NRF2; antioxidant
资金
- Natural Science Foundation of Yunnan Province, China [2016FB130]
- Science Foundation of Health and Family Planning Committee of Yunnan Province [2016NS066]
- National Natural Science Foundation of China [81560319]
Sirtuin 6 (SIRT6), a member of the sirtuin family of NAD(+)-dependent deacetylases, has been shown to produce beneficial effects in myocardial ischemia/reperfusion (l/R). However, the role of SIRT6 in cerebral l/R is largely unclear. In this study, we investigated the effects of SIRT6 overexpression in regulating l/R injury in a mouse cerebral l/R model in vivo and in oxygen-glucose-deprivation/reoxygenation (OGD/R)-stimulated neuro-2a neuroblastoma cells in vitro. We found that cerebral l/R (1 h/24 h) resulted in decreased SIRT6 expression in the cerebral cortex (P < 0.01). SIRT6 overexpression in the brain by in vivo gene transfer enhanced the antioxidant NRF2 signaling (P < 0.05), reduced oxidative stress (P < 0.05), and attenuated cerebral l/R-induced brain tissue damage and neurological deficits (P < 0.05). These neuroprotectlve effects of SIRT6 overexpression were abolished in NRF2 knockout mice. In neuro-2A neuroblastoma cells, SIRT6 overexpression increased total and nuclear NRF2 levels (P < 0.05), reduced oxidative stress (P < 0.05), and attenuated OGD/R-induced cell death (P < 0.05); these protective effects were blocked by NRF2 knockdown (P < 0.05). Moreover, in OGD/R-stimulated neuro-2A cells, SIRT6 overexpression produced similar protective effects to those induced by the antioxidant NAC, but no added benefits were detected when SIRT6 overexpression was used In combination with NAC (P > 0.05). These findings provide evidence that SIRT6 can protect the brain from cerebral l/R injury by suppressing oxidative stress via NRF2 activation. Thus, SIRT6 may serve as a potential therapeutic target for ischemic stroke. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
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