Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE
Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE
复制标题
Ghrelin 通过 GHSR-1 α/AMPK/Sirt1/PGC-1 α/UCP2 通路减轻新生儿 HIE 大鼠模型中的氧化应激和神经元凋亡
DOI：
10.1016/j.freeradbiomed.2019.07.001
复制
发表时间：
2019-09-01
影响因子：
7.4
通讯作者：
Zhang, John H.
中科院分区：
文献类型：
--
作者：
Huang, Juan;Liu, Wei;Zhang, John H.
Neuronal apoptosis induced by oxidative stress is one of the major pathological processes involved in neurological impairment after hypoxic-ischemic encephalopathy (HIE). Ghrelin, the unique endogenous ligand for the growth hormone secretagogue receptor-1 alpha (GHSR-1 alpha), could take an anti-apoptotic role in the brain. However, whether ghrelin can attenuate neuronal apoptosis by attenuating oxidative stress after hypoxia-ischemia (HI) insult remains unknown. To investigate the beneficial effects of ghrelin on oxidative stress injury and neuronal apoptosis induced by HI, ten-day old unsexed rat pups were subjected to HI injury and exogenous recombinant human ghrelin(rh-Ghrelin) was administered intranasally at 1 h and 24h after HI induction. [D-Lys(3)]-GHRP-6, a selective inhibitor of GHSR-1 alpha and Ex527, a selective inhibitor of GHSR-1 alpha were administered intranasally at 1 h before HI induction respectively. Small interfering ribonucleic acid (siRNA) for GHSR-1 alpha were administered by intracerebroventricular (i.c.v) injection at 24 h before HI induction. Neurological tests, immunofluorescence, MitoSox staining, Fluoro-Jade C staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and western blot experiments were performed. Our results indicated that ghrelin significantly improved neurobehavioral outcomes and reduced oxidative stress and neuronal apoptosis. Moreover, ghrelin treatment significantly promoted phosphorylation of AMPK, upregulated the expression of Sirt1, PGC-1 alpha, UCP2 and the ratio of Bcl2/Bax, while it downregulated cleaved caspase-3 levels. The protective effects of ghrelin were reversed by [D-Lys(3)]-GHRP-6, GHSR-1 alpha siRNA or Ex527. In conclusion, our data demonstrated that ghrelin reduced oxidative stress injury and neuronal apoptosis which was in part via the GHSR-1 alpha/AMPK/Sirt1/PGC-1 alpha/UCP2 signalling pathway after HI. Ghrelin may be a novel therapeutic target for treatment after neonatasl HI injury.
