Ghrelin protects dopaminergic neurons against MPTP neurotoxicity through promoting autophagy and inhibiting endoplasmic reticulum mediated apoptosis

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, the important pathology of PD due to the prominent loss of the dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) and striatum (STR). Although the etiology of PD is not fully understood, aggregation of α-synuclein, impaired Autophagy, and endoplasmic reticulum stress (ERS) are involved in the pathogenesis of PD. Previously it has been demonstrated that Ghrelin is a kind of peptide protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyran (MPTP)-induced neurotoxicity, but the detailed mechanism remains to be elucidated. In the present work, we investigated the effects of Ghrelin on Autophagy and ERS-mediated Apoptosis in the MPTP-lesioned PD mice model. We found that Ghrelin was neuroprotective against MPTP-induced dopaminergic neurodegeneration. Subsequently, we investigated Ghrelin inhibited the accumulation and phosphorylation of α-synuclein induced by MPTP. Moreover, Ghrelin promoted Autophagy indicated by the up-regulation of microtubule-associated protein 1 LIGHT Chain 3B-II/I (LC3B-II/I) and Beclin1, as well as decreasing the level of p62 in the SNpc and STR. Besides, the activation of the ERS-related Apoptosis signaling pathway including IRE1α and Caspase-12 signaling pathway induced by MPTP was suppressed by Ghrelin treatment. Furthermore, Ghrelin also decreased Caspase-3 expression. Taken together, our results indicated that Ghrelin may exert neuroprotective effects via regulating α-synuclein activities, enhancing Autophagy, and ameliorating ERS-mediated Apoptosis in MPTP-lesioned mice, which provides a new target for potential pharmacologic interventions of PD treatment in the future.