Ghrelin mitigates MPP + -induced cytotoxicity: involvement of ERK1/2-mediated Nrf2/HO-1 and endoplasmic reticulum stress PERK signaling pathway.

Parkinson's disease (PD) is a common progressive and multifactorial neurodegenerative disease. Current pharmacological therapies for PD are inadequate and often accompanied by serious side effects. In search of neuroprotective agents being considered to be beneficial to PD therapy. Ghrelin confers neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned PD model, but the underlying mechanism remains not fully elucidated. Here, we utilized human neuroblastoma SH-SY5Y cells exposed to MPP+ as a PD model to investigate the underlying mechanism of Ghrelin. In our present work, cell viability, cell apoptosis, oxidative stress-related indicators, and the level of Nrf2, HO-1, PERK, eIF2 alpha, ATF4, CHOP, and ERK1/2 were examined. The results showed that Ghrelin attenuated MPP+-induced change of cell viability, apoptosis, coupled with decreased Cytochrome c, caspase-9, and caspase-3 expressions. Consistently, Ghrelin suppressed MPP+-induced oxidative stress. Moreover, Ghrelin markedly enhanced Nrf2 expression and nuclear accumulation as well as HO-1 induction. Further investigations showed that Ghrelin significantly inhibited the endoplasmic reticulum stress PERK-eIF2 alpha-ATF4-CHOP pathway. Interestingly, we then found that Ghrelin promoted phosphorylation of ERK1/2, and pharmacological inhibition of ERK signaling abolished the cytoprotective effect of Ghrelin. Furthermore, we also found promoting the activation of the Nrf2/HO-1 pathway and suppressing of the PERK pathway were mediated by ERK1/2. These findings provided novel insights into the underlying mechanisms of Ghrelin exerted protective effect, suggesting its potential as a novel therapeutic strategy against PD.