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

Authors

  • Mir Ahamed Hossain,

    1. Departments of *Neurology, †Neuroscience and ‡Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §The Kennedy Krieger Research Institute, Baltimore, Maryland, USA
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  • Juliet C. Russell,

    1. Departments of *Neurology, †Neuroscience and ‡Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §The Kennedy Krieger Research Institute, Baltimore, Maryland, USA
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  • Raquel Gomes,

    1. Departments of *Neurology, †Neuroscience and ‡Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §The Kennedy Krieger Research Institute, Baltimore, Maryland, USA
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  • John Laterra

    1. Departments of *Neurology, †Neuroscience and ‡Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §The Kennedy Krieger Research Institute, Baltimore, Maryland, USA
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Address correspondence and reprint requests to Mir Ahamed Hossain, Department of Neurology, The Kennedy Krieger Research Institute, 707 N. Broadway, Baltimore, MD 21205, USA.
E-mail: hossain@kennedykrieger.org

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 (100 nm), 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.

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