Fibroblast growth factor-2 requires glial-cell-line-derived neurotrophic factor for exerting its neuroprotective actions on glutamate-lesioned hippocampal neurons

Mol Cell Neurosci. 2002 Jun;20(2):181-97. doi: 10.1006/mcne.2002.1134.

Abstract

FGF-2 is a potent neurotrophic factor for several populations of CNS neurons and has been shown to protect hippocampal neurons from glutamate-induced cell death in vitro and in vivo. Mechanisms underlying the neurotrophic and protective actions of FGF-2 have been resolved only in part. Using glutamate-treated cultured hippocampal neurons we show that FGF-2 shares its neuroprotective capacity with GDNF. Hippocampal neurons express glial-cell-line-derived neurotrophic factor (GDNF), its receptors c-Ret and the lipid-anchored GDNF family receptor-alpha1 (GFRalpha-1), and the FGF receptor 1 (FGFR I). Neutralizing antibodies to GDNF abolish the neuroprotective effect of FGF-2. In support of the notion that GDNF is required to permit the protective effects of FGF-2 we find that FGF-2 up-regulates GDNF and GFRalpha-1 in hippocampal neurons. Furthermore, FGF-2-induced GDNF causes enhanced phosphorylation of c-Ret and the signaling components Akt and Erk. A putative downstream target of FGF-2 and GDNF are bcl-2 gene family members, whose mRNAs are differentially up-regulated by the two factors. Together, these data suggest that GDNF is an important protective factor for glutamate-lesioned hippocampal neurons and an essential mediator of the neuroprotective actions of FGF-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Cell Death / drug effects*
  • Cell Death / physiology
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytokines / pharmacology
  • Drosophila Proteins*
  • Drug Interactions / physiology
  • Female
  • Fetus
  • Fibroblast Growth Factor 2 / metabolism
  • Fibroblast Growth Factor 2 / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Membrane Microdomains / metabolism
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phosphorylation
  • Pregnancy
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-ret
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptor Protein-Tyrosine Kinases / genetics
  • Signal Transduction / physiology

Substances

  • Antibodies
  • Cytokines
  • Drosophila Proteins
  • Gdnf protein, rat
  • Gfra1 protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Fibroblast Growth Factor 2
  • Glutamic Acid
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ret protein, rat