Neurotrophic rationale in glaucoma: a TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo.
Glaucoma is a major cause of vision impairment, which arises from the sustained and progressive apoptosis of retinal ganglion cells (RGC), with ocular hypertension being a major risk or co-morbidity factor. Because RGC death often continues after normalization of ocular hypertension, growth factor-mediated protection of compromised neurons may be useful. However, the therapeutic use of nerve growth factor (NGF) has not proven effective at delaying RGC death in glaucoma. We postulated that one cause for the failure of NGF may be related to its binding to two receptors, TrkA and p75. These receptors have distinct cellular distribution in the retina and in neurons they induce complex and sometimes opposing activities. Here, we show in an in vivo therapeutic model of glaucoma that a selective agonist of the pro-survival TrkA receptor was effective at preventing RGC death. RGC loss was fully prevented by combining the selective agonist of TrkA with intraocular pressure-lowering drugs. In contrast, neither NGF nor an antagonist of the pro-apoptotic p75 receptor protected RGCs. These results further a neurotrophic rationale for glaucoma.
Shi
ZhiHua
Z
Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
Birman
Elena
E
Saragovi
H Uri
HU
D000818:Animals; D002232:Carbocyanines; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005260:Female; D005901:Glaucoma / Q000150:complications*; D007429:Intraocular Pressure / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000819:agonists / Q000378:metabolism; D020917:Receptor, trkA / Q000819:agonists* / Q000378:metabolism; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013266:Stilbamidines
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C035005:3,3'-dihexadecylindocarbocyanine; D002232:Carbocyanines; D018696:Neuroprotective Agents; D010455:Peptides; D020800:Receptor, Nerve Growth Factor; D013266:Stilbamidines; D020932:Nerve Growth Factor; D020917:Receptor, trkA