Neuroprotection by scatter factor/hepatocyte growth factor and FGF-1 in cerebellar granule neurons is phosphatidylinositol 3-kinase/akt-dependent and MAPK/CREB-independent

J Neurochem. 2002 Apr;81(2):365-78. doi: 10.1046/j.1471-4159.2002.00837.x.

Abstract

Neuroprotective actions of scatter factor/hepatocyte growth factor (SF/HGF) have not been described. We examined the effects of SF/HGF in comparison to acidic fibroblast growth factor-1 (FGF-1) on N-methyl-D-aspartate (NMDA) and quinolinic acid (QUIN)-induced excitotoxicity in primary cerebellar granule neurons. Exposure to NMDA or QUIN for 24 h resulted in concentration-dependent cell death (p < 0.001) that was completely attenuated (p < 0.001) by pre-treatment of cells with SF/HGF (50 ng/mL) or FGF-1 (40 ng/mL). SF/ HGF and FGF-1 activated both Akt and MAP-kinase > threefold (p < 0.001). Neither SF/HGF nor FGF-1 activated cyclic AMP-response element binding protein (CREB), a downstream target of MAP-kinase, whereas brain-derived neurotrophic factor (BDNF) activated both MAP-kinase and CREB in granule neurons. Neuroprotection against NMDA or QUIN by SF/HGF and FGF-1 was negated by the addition of LY294002 (10 microM) or wortmannin (100 microM), two distinct inhibitors of phosphatidylinositol 3-kinase (P13-K), but not by the MAP-kinase kinase (MEK) inhibitor PD98059 (33 microm). Likewise, expression of a dominant-negative mutant of Akt (Akt-kd) completely prevented the neuroprotective actions of SF/HGF and FGF-1. Overexpression of a constitutively activated Akt (Akt-myr) or wild-type Akt (wtAkt) attenuated excitotoxic cell death. These data show that both SF/HGF and FGF-1 protect cerebellar granule neurons against excitotoxicity with similar potency in a P13-K/Akt-dependent and MAP-kinase/CREB-independent manner.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / drug effects*
  • Cerebellum / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytoprotection
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / toxicity
  • Fibroblast Growth Factor 1 / pharmacology*
  • Hepatocyte Growth Factor / pharmacology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-met / biosynthesis
  • Rats
  • Rats, Inbred Lew

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Fibroblast Growth Factor 1
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases