Recent studies suggest that hepatocyte growth factor (HGF) functions as a neurotrophic factor in the central nervous system. In this study, we investigated the neuroprotective effect of HGF and its mechanism of action. We used cultured cerebellar granule neurons that underwent apoptosis when the culture medium was changed from that containing serum with 25 mM K(+) to serum-free medium containing 5 mM K(+), and HGF prevented apoptotic cell death. HGF stimulated both mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI3)-kinase activity in cerebellar granule neurons. Two specific inhibitors of PI3-kinase, wortmannin and LY294002, efficiently blocked this neuroprotective effect of HGF. In contrast, PD98059, a selective inhibitor of MAP kinase kinase (MEK), did not affect the anti-apoptotic effect of HGF. The downstream signal of PI3-kinase in this protection was further investigated. HGF-induced phosphorylation of Akt and pretreatment of the cells with wortmannin completely impaired Akt activation. These results suggest that HGF prevents apoptosis in cerebellar granule neurons via the PI3-kinase/Akt pathway.
Copyright 2000 Wiley-Liss, Inc.