Protective effects of glial cell line-derived neurotrophic factor in ischemic brain injury.
Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to have trophic activity on dopaminergic neurons. Recent studies indicate that GDNF can protect the cerebral hemispheres from damage induced by middle cerebral arterial ligation. We found that such neuroprotective effects are mediated through specific GDNF receptor alpha-1 (GFRalpha1). Animals with a deficiency in GFRalpha-1 have less GDNF-induced neuroprotection. Ischemia also enhances nitric oxide synthase (NOS) activity, which can be attenuated by GDNF. These.data suggest that GDNF can protect against ischemic injury through a GFRalpha-1/NOS mechanism. We also found that the receptor for GDNF, GFRalpha1, and its signaling moiety c-Ret were upregulated, starting immediately after ischemia. This upregulation suggests that activation of an endogenous neuroprotective mechanism occurs so that responsiveness of GDNF can be enhanced at very early stages during ischemia.
Wang
Y
Y
National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. ywang@intra.nida.nih.gov
Chang
C F
CF
Morales
M
M
Chiang
Y H
YH
Hoffer
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000601:surgery; D002545:Brain Ischemia / Q000503:physiopathology*; D002117:Calcitriol / Q000494:pharmacology; D029721:Drosophila Proteins; D016332:Fetal Tissue Transplantation; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D016202:N-Methylaspartate / Q000378:metabolism; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D009569:Nitric Oxide; D016202:N-Methylaspartate; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D002117:Calcitriol