Retinal ganglion cell loss in aging mice.

Mount Sinai School Of Medicine Of Nyu, New York NY

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Abstract

DESCRIPTION (provided by applicant): The primary aim of this project is to characterize the time-course and pattern of retinal ganglion cell (RGC) death in the highly inbred DBA 2J mouse and to establish this mouse as an in-vivo test system for potential neuroprotective interventions (drugs, gene-therapy, etc.). DBA/2 mice spontaneously develop a pigmentary glaucoma with elevated ocular pressure (IOP). There is a significant gender-difference in the time of onset and progression of retinal pathology. Severe IOP-induced loss of RGC occurs much earlier in life in the female DBA/2 mouse than the male or very old normal mice (C57 BL/6J). Experiments involving orchidectomy, supplementation with estrogen, testosterone or progesterone and chronic treatment with aromatase inhibitors are aimed to support the hypothesis that aromatase-derived estrogen (from testosterone) delays retinal pathology in male DBA/2 mice. The relationship of RGC loss to the elevated IOP history of individual eyes and to the degenerative changes in the superior colliculus of the brain receiving input from that eye will also be investigated. Mice chronically treated (3-4 months) with several classes of drugs that are partially effective in short-term treatments of acute induced rat RGC death models, will be evaluated by mapping of RGC in the entire retina. The classes of drugs to be tested include an alpha-adrenergic agonist, a beta-adrenergic antagonist, inhibitors of the NOS-2 enzyme, and the anti-Parkinson's agents deprenyl and memantine. The drug experiments are aimed at establishing proof-of-principle that agents having neuroprotective properties in cultures or acute model systems can be effective in a slow, spontaneous neurodegenerative condition, such as RGC death, when administered as chronic systemic therapy.