Glaucoma is a disease marked in the majority of cases by a significant elevation of intraocular pressure. This intolerable level of pressure compromises the optic nerve, and leads to the loss of retinal ganglion cells. Accordingly, the majority of therapeutic interventions are specifically directed at pressure control. This grant suggests a second etiology for the neuronal loss seen in glaucoma The Principal Investigator has demonstrated an elevated level of the excitatory amino acid glutamate in the vitreous of patients with glaucoma. This agent, known to be toxic to retinal ganglion cells, may therefore contribute to the cell death seen in glaucoma. It is suggested that neuronal injury engendered by this excitatory amino acid is mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. This form of toxicity has been well documented in a wide variety of central nervous system (CNS) diseases; given that retinal ganglion cells are indeed part of the CNS, it is not surprising that glutamate is toxic to these neurons as well. If glutamate indeed plays a role in glaucomatous visual loss, this suggests several new therapies for the management of the patient with glaucoma. This grant proposes to explore several clinically safe inhibitors of NMDA toxicity. Initial studies will be performed in vitro; however the demonstrated clinical utility of the proposed drugs for other conditions should expedite their use in a clinical scenario in the future. This grant proposes the following: (l) In Preliminary Studies, elevated vitreous levels of glutamate are reported in a limited number of patients with glaucoma. This data base will be expanded to confirm these preliminary results. More samples will also establish if stratification by glaucoma diagnosis or other factors identifies a subpopulation of glaucoma patients with higher levels of glutamate that will derive particular benefit from treatment with the proposed agents. (2) To develop a rodent model of chronic glutamate/NMDA retinal toxicity, as well as testing in vivo the compounds characterized in vitro under (3) & (4). (3) To test adamantane derivatives, such as memantine (which we have shown is an NMDA open-channel blocker), for their ability to prevent acute NMDA receptor-mediated neurotoxicity in retinal ganglion cells incubated with glutamate or NMDA. (4) To characterize and test reagents, including nitric oxide (NO)- producing drugs and glutathione, that down regulate NMDA receptor activity by oxidation of a redox modulatory site, in order to prevent chronic NMDA receptor-mediated neurotoxicity.
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