Protective effect of urocortin on 1-methyl-4-phenylpyridinium-induced dopaminergic neuronal death

Recent studies have indicated that the corticotropin releasing hormone (CRF)-related peptide, urocortin, restores key indicators of damage in animal models for Parkinson's disease (PD). However, the molecular mechanism for the neuroprotective effect of urocortin is unknown. 1-Methy-4-phenylpyridinium (MPP(+)) induces dopaminergic neuronal death. In the present study, MPP(+)-induced neuroblastoma SH-SY5Y cell death was significantly attenuated by urocortin in a concentration-dependent manner. The protective effect of urocortin involved the activation of CRF receptor type 1, resulting in the increase of cyclic AMP (cAMP) levels. Various cAMP-enhancing reagents mimicked the effect of urocortin, while inhibitors for protein kinase A (PKA) blocked the effect of urocortin, strongly implicating the involvement of cAMP-PKA pathway in the neuroprotective effect of urocortin on MPP(+)-induced cell death. As the downstream of this signal pathway, urocortin promoted phosphorylation of both glycogen synthase kinase 3β and extracellular signal-regulated kinases, which are known to promote cell survival. These neuroprotective signaling pathways of urocortin may serve as potential therapeutic targets for PD.