Hepatocyte growth factor protects cultured rat cerebellar granule neurons from apoptosis via the phosphatidylinositol-3 kinase/Akt pathway

Recent studies suggest that hepatocyte growth factor (HGF) functions as a n eurotrophic factor in the central nervous system. In this study, we investi gated the neuroprotective effect of HGF and its mechanism of action. We use d cultured cerebellar granule neurons that underwent apoptosis when the cul ture medium was changed from that containing serum with 25 mM K+ to serum-f ree medium containing 5 mM K+, and HGF prevented apoptotic cell death. HGF stimulated both mitogen-activated protein (MAP) kinase and phosphatidylinos itol-3 (Pl3)-kinase activity in cerebellar granule neurons. Two specific in hibitors of Pl3-kinase, wortmannin and LY294002, efficiently blocked this n europrotective effect of HGF. In contrast, PD98059, a selective inhibitor o f MAP kinase kinase (MEK), did not affect the anti-apoptotic effect of HGF. The downstream signal of Pl3-kinase in this protection was further investi gated. HGF-induced phosphorylation of AM and pretreatment of the cells with wortmannin completely impaired Akt activation. These results suggest that HGF prevents apoptosis in cerebellar granule neurons via the Pl3-kinase/Akt pathway. (C) 2000 Wiley-Liss, Inc.