Neuroprotection by Orexin-A via HIF-1α induction in a cellular model of Parkinson's disease

Orexin-A, a neuropeptide secreted by hypothalamic neurons, may be neuroprotective in many neurological conditions such as cerebral ischaemia. One mechanism postulated to be involved in the neuroprotection by Orexin-A is the induction of hypoxia inducible factor 1 alpha (HIF-1 alpha). Parkinson's disease (PD) is a progressive neurodegenerative disorder and mitochondrial dysfunction has been demonstrated to play a role in its pathogenesis. Mitochondrial dysfunction may cause reduction of O-2 consumption and subsequently activate prolyl hydroxylase, which leads to decreased level of HIF-1 alpha. In this study, we used MPP+-treated SH-SY5Y cells as an in vitro cellular model of PD to test the role of Orexin-A as an inducer of HIF-1 alpha. Our results showed that Orexin-A not only induced HIF-1 alpha but also activated downstream targets of HIF-1 alpha, such as vascular endothelial growth factor and erythropoietin. Thus, Orexin-A treatment attenuated MPP+-induced cell injury and this effect was blocked when HIF-1 alpha was suppressed. Hence, we conclude that induction of HIF-1 alpha is one of the mechanisms involved in the neuroprotection by Orexin-A. (C) 2014 Elsevier Ireland Ltd. All rights reserved.