Glaucoma is an optic neuropathy with cupping of the optic disk, degeneration of retinal ganglion cells, and characteristic visual field loss. Because elevated intraocular pressure (IOP) is a major risk factor for progression of glaucoma, treatment has been based on lowering IOP. We previously demonstrated inducible nitric-oxide synthase (NOS-2) in the optic nerve heads from human glaucomatous eyes and from rat eyes with chronic, moderately elevated IOP. Using this rat model of unilateral glaucoma, we treated a group of animals for 6 months with aminoguanidine, a relatively specific inhibitor of NOS-2, and compared them with an untreated group. At 6 months, untreated animals had pallor and cupping of the optic disks in the eyes with elevated IOP. Eyes of aminoguanidine-treated animals with similar elevations of IOP appeared normal. We quantitated retinal ganglion cell loss by retrograde labeling with Fluoro-Gold. Glaucoma is characterized by excavation of the optic disk, loss of retinal ganglion cells, and a specific pattern of visual field loss (1, 2). Because elevated intraocular pressure (IOP) is a major risk factor for progression of this optic neuropathy, pharmacological and surgical treatment of glaucoma has been aimed at lowering IOP (3, 4). Recently, the cellular changes in the optic nerve and retina that can lead to retinal ganglion cell degeneration have been studied to determine the relevant mechanisms. A major objective of this work is to devise potential, therapeutic approaches to prevent retinal ganglion cell loss. Using laboratory models, including ischemia, optic nerve transection, optic nerve crush, and culture of retinal ganglion cells, various pharmacological agents have been tested as potential neuroprotective approaches (5-8). Although there have been no pharmacological studies in an animal model that closely resembles human glaucoma, these approaches have suggested that antagonism of excitotoxicity or supplementation of neurotrophic factors can protect, at least temporarily in animal models, retinal ganglion cells from degeneration.To develop medical therapies for glaucoma based on pharmacological neuroprotection, our research has focused on an underlying mechanism that has been demonstrated in human glaucomatous tissue and that has the neurotoxic potential to cause glaucomatous optic nerve degeneration and loss of retinal ganglion cells. Our laboratory has demonstrated previously that the inducible isoform of nitric-oxide synthase (NOS-2) is present in astrocytes in the optic nerve heads from glaucomatous human eyes (9) and from rat eyes with chronic, moderately elevated IOP (10), but not in normal eyes. We have postulated that excessive nitric oxide causes neurodegeneration of the axons of the retinal ganglion cells in glaucoma. To test our hypothesis and to demonstrate the feasibility of using an inhibitor of NOS-2 as a pharmacological neuroprotective agent to treat glaucoma, we have tested aminoguanidine, a relatively specific inhibitor of NOS-2, in a rat model of glaucoma in whi...
