Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor.
In the present study we localized glial cell line-derived neurotrophic factor (GDNF), and the high affinity receptor for GDNF (GFRalpha-1) in the rat retina. We also examined the effects of neurturin on the survival of axotomized retinal ganglion cells (RGCs) and compared neurturin-mediated RGC rescue to GDNF and brain-derived neurotrophic factor (BDNF) neuroprotection. We administered combined injections of neurturin with BDNF or GDNF in order to determine if these factors rescue RGCs by different mechanisms. GDNF immunoreactivity was localized to RGCs, photoreceptors, and retinal pigment epithelial cells. GFRalpha-1 immunoreactivity was localized to RGCs, Müller cells, and photoreceptors. RGC densities in control retinas decreased from the original value of 2481+/-121 (RGCs/mm(2)+/-S.D.) to 347+/-100 at 14 days post-axotomy. Neurturin treatment significantly increased RGC survival after axotomy (745+/-94) similar to GDNF (868+/-110). BDNF treatment resulted in higher RGC survival (1109+/-156) than either neurturin or GDNF. Combined administration of neurturin with BDNF had additive effects on the survival of axotomized RGCs (1962+/-282), similar to combined administration of GDNF and BDNF (1825+/-269). Combined administration of neurturin and GDNF (1265+/-178) had an enhanced effect on RGC survival. These results suggest that neurturin, GDNF, and BDNF act independently to rescue injured RGCs. Our results also suggest that RGCs and retinal Müller cells may be responsive to GDNF because they both express GFRalpha-1. The present findings have implications for the rescue of injured retinal ganglion cells, as well as other CNS neurons that are responsive to neurturin, GDNF, and BDNF, including midbrain dopaminergic neurons and motor neurons.
Koeberle
Paulo D
PD
McMaster University, Anatomy, HSC 1R1, 1200 Main Strreet West, L8N 3Z5, Hamilton, ON, Canada.
Ball
Alexander K
AK
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D016900:Neurofilament Proteins / Q000378:metabolism; D051101:Neurturin; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D029721:Drosophila Proteins; D004338:Drug Combinations; C495041:Gdnf protein, rat; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D051101:Neurturin; C495057:Nrtn protein, rat; D011518:Proto-Oncogene Proteins; C051774:neurofilament protein H; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila