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-1α (GHSR-1α),
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 24 h after HI induction. [D-Lys 3 ]-GHRP-6, a selective inhibitor
of GHSR-1α and Ex527, a selective inhibitor of GHSR-1α were administered intranasally
at 1 h before HI induction respectively. Small interfering ribonucleic acid (siRNA)
for GHSR-1α 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-1α, 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-1α siRNA or Ex527. In conclusion, our data demonstrated that ghrelin
reduced oxidative stress injury and neuronal apoptosis which was in part via the GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2
signalling pathway after HI. Ghrelin may be a novel therapeutic target for treatment
after neonatasl HI injury.