Neurotrophic rationale in glaucoma: a TrkA agonist, but not NGF or a p75 antagonist, protects retinal ganglion cells in vivo.

Abstract

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.

• Authors: ZhiHua Shi, Elena Birman, H Uri Saragovi
• Journal: Developmental neurobiology (Dev Neurobiol) Vol. 67 Issue 7 Pg. 884-94 (Jun 2007) ISSN: 1932-8451 [Print] United States
• PMID: 17506493 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
• 3,3'-dihexadecylindocarbocyanine
• Carbocyanines
• Neuroprotective Agents
• Peptides
• Receptor, Nerve Growth Factor
• Stilbamidines
• Nerve Growth Factor
• Receptor, trkA

Topics

• Animals
• Carbocyanines
• Cell Death (drug effects, physiology)
• Cell Survival (drug effects, physiology)
• Female
• Glaucoma (complications)
• Intraocular Pressure (drug effects, physiology)
• Nerve Degeneration (drug therapy, etiology, physiopathology)
• Nerve Growth Factor (pharmacology)
• Neuroprotective Agents (pharmacology)
• Peptides (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Nerve Growth Factor (agonists, metabolism)
• Receptor, trkA (agonists, metabolism)
• Retinal Degeneration (drug therapy, etiology, physiopathology)
• Retinal Ganglion Cells (cytology, drug effects, metabolism)
• Stilbamidines