Nesfatin-1 protects dopaminergic neurons against MPP(+)/MPTP-induced neurotoxicity through the C-Raf–ERK1/2-dependent anti-apoptotic pathway

Several brain-gut peptides have been reported to have a close relationship with the central dopaminergic system; one such brain-gut peptide is nesfatin-1. Nesfatin-1 is a satiety peptide that is predominantly secreted by X/A-like endocrine cells in the gastric glands, where ghrelin is also secreted. We previously reported that ghrelin exerted neuroprotective effects on nigral dopaminergic neurons, which implied a role for ghrelin in Parkinson’s disease (PD). In the present study, we aim to clarify whether nesfatin-1 has similar effects on dopaminergic neurons both in vivo and in vitro. We show that nesfatin-1 attenuates the loss of nigral dopaminergic neurons in the 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In addition, nesfatin-1 antagonized 1-methyl-4-phenylpyridillium ion (MPP(+))-induced toxicity by restoring mitochondrial function, inhibiting cytochrome C release and preventing caspase-3 activation in MPP(+)-treated MES23.5 dopaminergic cells. These neuroprotective effects could be abolished by selective inhibition of C-Raf and the extracellular signal-regulated protein kinase 1/2 (ERK1/2). Our data suggest that C-Raf-ERK1/2, which is involved in an anti-apoptotic pathway, is responsible for the neuroprotective effects of nesfatin-1 in the context of MPTP-induced toxicity. These results imply that nesfatin-1 might have therapeutic potential for PD.