Abstract
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.
Highlights
Several brain-gut peptides, such as neurotensin, ghrelin, and glucagon-like peptide-1, have been reported to have a close relationship with the central dopaminergic system[1,2]
In accordance with the above results, immunohistochemistry staining of the stiatum showed that the number of tyrosine hydroxylase (TH)-immunoreactivity (TH+) fibers was markedly reduced in mice after 5 days of MPTP injections; pretreatment of mice with 100 ng, 200 ng, and 400 ng nesfatin-1protected most TH+fibers from MPTP-induced toxicity (Fig. 1D)
We demonstrated that nesfatin-1 protects dopaminergic neurons against MPTP-induced neurotoxicity in C57BL/6 mice and MPP+-induced cytotoxicity in MES23.5 cells, and further elucidated that the neuroprotective effect of nesfatin-1 was mediated via activation of the C-Raf-extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling cascade, which inhibited apoptosis induced by mitochondrial dysfunction
Summary
Several brain-gut peptides, such as neurotensin, ghrelin, and glucagon-like peptide-1, have been reported to have a close relationship with the central dopaminergic system[1,2]. We reported that ghrelin, which is secreted by X/A-like cells in the gastric glands, showed neuroprotective effects on dopaminergic neurons exposed to the toxin 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) both in vivo and in vitro via an anti-apoptotic effect mediated by the ghrelin-protein kinase C (PKC) signaling pathway[9,10,11]. Together with data from other groups, showed that nesfatin-1 could exert various effects in the central nervous system, its receptors have yet to be cloned, they are speculated to be G-protein-coupled receptors acting through Gi and Gs17,31. This lack of knowledge about nesfatin-1 receptors makes it quite difficult to decipher the central role of nesfatin-1.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
