Nerve growth factor prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cell death via the Akt pathway by suppressing caspase-3-like activity using PC12 cells: Relevance to therapeutical application for Parkinson'sdisease

Nerve growth factor (NGF) mediates a variety of nerve cell actions through receptor tyrosine kinase TrkA. It has been revealed that the Akt pathway co ntributes to the prevention of apoptosis. It is thought that Parkinson's di sease involves apoptosis, and NGF prevents apoptosis in an in vivo model sy stem. However, there is no evidence that the Akt pathway helps to prevent p arkinsonism. Here, we report that NGF prevents apoptosis induced by 1-methy l-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in PC12 cells as an in vitro m odel system of parkinsonism and that this survival effect diminishes on add ition of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase. I mmunocytochemical analysis revealed that 1 mM MPTP-treated cells or dominan t negative Akt-expressing cells, to which were added NGF and MPTP, undergo apoptosis. Moreover, the caspase-3-like activity is increased by addition o f MPTP or MPTP with NGF and LY294002. The importance of another signal path way is shown by PD98059, a specific inhibitor of MAP kinase (MAPK) kinase, but PD98059 does not alter the survival effect in this model system. These results indicate that the Akt pathway helps to prevent parkinsonism by supp ressing caspase-3-like activity, but the MAPK pathway is not involved in th e NGF-dependent survival enhancing effect in this model system. (C) 2001 Wi ley-Liss, Inc.