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

Mir Ahamed Hossain, Juliet C. Russell, Raquel G Hernandez, John J Laterra

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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 μM) or wortmannin (100nM), two distinct inhibitors of phosphatidylinositol 3-kinase (PI3-K), but not by the MAP-kinase kinase (MEK) inhibitor PD98059 (33 μM). 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 PI3-K/Akt-dependent and MAP-kinase/CREB-independent manner.

Original languageEnglish (US)
Pages (from-to)365-378
Number of pages14
JournalJournal of Neurochemistry
Volume81
Issue number2
DOIs
Publication statusPublished - 2002

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Keywords

  • Akt
  • Cerebellar granule neurons
  • Excitotoxicity
  • Mitogen-activated protein kinase
  • Neuroprotection
  • Neurotrophic factors

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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