The inherent, age-dependent loss of retinal ganglion cells is related to the lifespan of the species.

Retinal ganglion cells are neurons that transmit visual information from the retina to the brain. With age, there is an inherent loss of retinal ganglion cells that we have quantitated by retrograde labeling of these neurons. In adult mice, the loss of retinal ganglion cells is approximately 2.3% per month; in adult rats, the loss of retinal ganglion cells is approximately 1.5% per month. The total losses of these neurons over the average lifespans of mice and rats are similar to those which have been reported in monkeys and humans. Furthermore, caloric restriction, which extends the lifespans of mice and rats, slows the temporal age-related loss of retinal ganglion cells. Thus, the total age-dependent losses of these neurons appear to be approximately the same over the lifespans of these mammalian species.

Loss of retinal ganglion cells following retinal ischemia: the role of inducible nitric oxide synthase.

Following experimental, transient, retinal ischemia in the rat, there is loss of retinal neurons, which occurs over several weeks. Retinal ganglion cells (RGCs) are particularly susceptible and there is early, massive degeneration of these neurons after ischemia. We have determined the early mechanisms by which RGCs are killed following ischemia. Retinal ischemia/reperfusion was produced in rats by transient unilateral elevation of intraocular pressure above systolic blood pressure. Retinas were studied by immunohistochemistry for the presence of inducible nitric oxide synthase (NOS-2) at several time points post-ischemia and specific cell types were identified. Rats were also treated orally with L -N(6) -(1-iminoethyl)lysine 5-tetrazole amide (SC-51), a prodrug of an inhibitor of NOS-2 or with aminoguanidine (AG) for a period of 14 days. Retrograde labelling with Fluoro-Gold quantitated the loss of RGCs. NOS-2 was not present in the normal retina and was not present in the eyes that were contralateral to the ischemic eyes. Within 24hr after ischemia, polymorphonuclear leukocytes containing NOS-2 had entered the ganglion cell layer and surrounded RGCs. Within 5 days after ischemia, NOS-2 was present in many inner retina cells and in invading monocytes in the vitreous. Between 7 and 14 days post-ischemia, there were few hematogenous cells in the retina but NOS-2 was sparsely detectable in microglia and other cells of the inner retina. Two weeks after ischemia, rat eyes lost approximately 50% of the RGCs. Treatment with AG for 14 days following ischemia was partially neuroprotective; approximately 28% of the RGCs were lost. Treatment with SC-51 for 14 days following ischemia almost completely prevented the loss of RGCs. Thus, within 24hr following ischemia, polymorphonuclear leukocytes containing NOS-2 attack and kill neurons in the ganglion cell layer. For 2 weeks after ischemia, NOS-2 appears transiently in the retina in several different cell types at different times. Continuous pharmacological treatment with inhibitors of NOS-2 activity during the 2 weeks post-ischemia period provides significant neuroprotection against the loss of RGCs.

A prodrug of a selective inhibitor of inducible nitric oxide synthase is neuroprotective in the rat model of glaucoma.

PURPOSE: To test the hypothesis that nitric oxide, synthesized by inducible nitric oxide synthase, causes degeneration of retinal ganglion cells in an animal model of glaucoma. METHODS: Rats with unilateral, chronic, moderately elevated intraocular pressure were treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of inducible nitric oxide synthase. The loss of retinal ganglion cells was quantitated as an indicator of glaucomatous damage. RESULTS: At the end of seven months, rat eyes with chronic, moderately elevated intraocular pressure lost approximately 20,000 retinal ganglion cells. Treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide for seven months completely prevented the loss of retinal ganglion cells in eyes with chronic, moderately elevated intraocular pressure. When treatment with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide was delayed and started after three months of chronic, moderately elevated intraocular pressure, further loss of retinal ganglion cells was prevented. CONCLUSION: Pharmacological neuroprotection with a selective inhibitor of inducible nitric oxide synthase may be useful for the treatment of glaucoma.