Apelin-13 Protects Dopaminergic Neurons against Rotenone—Induced Neurotoxicity through the AMPK/mTOR/ULK-1 Mediated Autophagy Activation

Abstract

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Several brain–gut peptides are able to exert neuroprotective effects on the nigrostriatal dopaminergic system. Apelin-13 is a neuropeptide, conveying potential neuroprotective activities. However, whether, and how, apelin-13 could antagonize rotenone-induced neurotoxicity has not yet been elucidated. In the present study, rotenone-treated SH-SY5Y cells and rats were used to clarify whether apelin-13 has protective effects on dopaminergic neurons, both in vivo and in vitro. The results showed that apelin-13 could protect SH-SY5Y cells from rotenone-induced injury and apoptosis. Apelin-13 was able to activate autophagy, and restore rotenone induced autophagy impairment in SH-SY5Y cells, which could be blocked by the autophagy inhibitor 3-Methyladenine. Apelin-13 activated AMPK/mTOR/ULK-1 signaling, AMPKα inhibitor compound C, as well as apelin receptor blockage via siRNA, which could block apelin-13-induced signaling activation, autophagy activation, and protective effects, in rotenone-treated SH-SY5Y cells. These results indicated that apelin-13 exerted neuroprotective properties against rotenone by stimulating AMPK/mTOR/ULK-1 signaling-mediated autophagy via the apelin receptor. We also observed that intracerebroventricular injection of apelin-13 could alleviate nigrostriatal dopaminergic neuron degeneration in rotenone-treated rats. Our findings provide new insights into the mechanism by which apelin-13 might attenuate neurotoxicity in PD.

Physical Exercise-Induced Myokines in Neurodegenerative Diseases

“…The role of apelin in NDs has only been studied recently. The results from these studies, which have been mainly focused on AD and PD using rodent models or cellular models, have suggested that apelin has beneficial effects on these diseases through various pathways [59][60][61][62][63][64][65][66][67]. One study has shown that apelin deficiency can accelerate ALS-like phenotype in an SOD1 (G93A) mouse model [68].…”

Research Progress on Mechanism of Neuroprotective Roles of Apelin-13 in Prevention and Treatment of Alzheimer’s Disease

“…Apelin-13 inhibits rotenone and Aβ induced injury and apoptosis in SH-SY5Y cells [38,39]. It is also known that apelin-13 blocks apoptosis and excitotoxicity in mice with ischemic brain injury [40,41].…”

Impact of the apelin/APJ axis in the pathogenesis of Parkinson’s disease with therapeutic potential

“…Apelin‐13 has been shown to act neuroprotectively in in vitro models of PD, by activating autophagy through the upregulation of AMPK/mTOR/ULK1 signaling pathway (Chen et al., 2020). These effects were accompanied by a reduction of rotenone‐induced α‐synuclein overexpression (Chen et al., 2020).…”

“…Apelin‐13 has been shown to act neuroprotectively in in vitro models of PD, by activating autophagy through the upregulation of AMPK/mTOR/ULK1 signaling pathway (Chen et al., 2020). These effects were accompanied by a reduction of rotenone‐induced α‐synuclein overexpression (Chen et al., 2020). Regarding the underlying molecular mechanisms, apelin‐13 was indicated to stimulate the phosphorylation of AMPKα and ULK1, as well as suppress mTOR phosphorylation in these cells (Chen et al., 2020).…”

“…These effects were accompanied by a reduction of rotenone‐induced α‐synuclein overexpression (Chen et al., 2020). Regarding the underlying molecular mechanisms, apelin‐13 was indicated to stimulate the phosphorylation of AMPKα and ULK1, as well as suppress mTOR phosphorylation in these cells (Chen et al., 2020). Apelin‐13/APJ interaction, AMPK/mTOR/ULK1 signaling pathway, and subsequent autophagy enhancement were essential for the protective role of apelin‐13 in these cells (Chen et al., 2020).…”