Protective effect of urocortin on 1-methyl-4-phenylpyridinium-induced dopaminergic neuronal death |
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| Authors: | Yonjung Kim Myoung Kyu Park Sungkwon Chung |
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| Institution: | (1) Department of Psychiatry, University of Pennsylvania, 125 South 31st Street, Room 2204, Philadelphia, PA 19104, USA;(2) Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA;(3) Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA;(4) Department of Pharmacology, National University of Ireland, Galway, Ireland;(5) Department of Anesthesiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; |
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| Abstract: | 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. |
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