Nitric-oxide synthase and neurodegeneration/neuroprotection.

Glaucoma is an optic neuropathy in which the retinal ganglion cells and their axons, which package and transmit visual impulses from the photoreceptors and associated retinal interneurons to the brain, die individually or in small groups, typically over many years (Figs. 1 and 2) (1). The resulting functional deficit is the second leading cause of irreversible visual loss in the U.S., and the most common cause among African-Americans. In its most prevalent form, the condition is strongly dependent upon age, race, and family history. Approximately 3–5% of White Americans, 10% of AfricanAmericans, and 20% of Afro-Caribbeans over the age of 70 years have the disease (2–5). As lifespan and the proportion of the population comprising the aged increase, so will the number and proportion afflicted. Intraocular pressure (IOP) plays a causal, albeit not necessarily exclusive, role in most cases of glaucomatous visual loss; the higher the IOP the greater the risk (4, 6). There is controversy about whether the primary insult occurs at the level of the axon or the cell body, and the pathophysiology of pressure-induced glaucomatous optic neuropathy is unclear and fiercely debated (7–11). Leading candidate theories include obstruction of axoplasmic flow within the retinal ganglion cell axons at the lamina cribrosa (the connective tissue plate at the back of the eye where the axons coalesce to form the optic nerve ‘‘head’’ or ‘‘disk,’’ from whence they continue as the optic nerve through the orbit and into the brain); compromise of the optic nerve microcirculation at the level of the lamina; and alterations in the laminar glial cells and connective tissues. Secondary insults (e.g., excitotoxicity caused by glutamate or glycine released from injured neurons, growth factor deprivation, oxidative damage caused by overproduction of reactive oxygen species) may contribute. Whatever the initial injury site and the initial and subsequent mechanisms (Table 1 lists various possibilities), the end stage of the process is death of the retinal ganglion cell by means of the triggering of an apoptosis program (12, 13), akin to that which eliminates 50% of the retinal ganglion cells during normal developmental organization of the visual pathway (9). All present glaucoma therapy is directed at lowering IOP (6). However, assaulting or bypassing the anterior eye tissues, which produce and drain the fluid aqueous humor, and thereby determine and regulate IOP, completely neglects the retinal ganglion cells and their axons, whose dysfunction and death are directly responsible for the visual loss. Only recently has knowledge of the mechanisms of neuronal death and its prevention, delay, or even reversal after a variety of insults reached the point where we can seriously entertain the possibility of glaucoma therapy directed at the retinal ganglion cell bodies or axons themselves. Studies in cultured neurons (including retinal ganglion cells) and in vivo models of mechanical (crush, transection), ischemic, and pharmacologic (e.g., intraocular glutamate injection) optic nerve or brain injury have suggested various strategies for neuroprotection, neurorescue, and neuroregeneration (14–21) (Table 2). However, none of these strategies had been tested, much less shown effective, in a glaucomatous animal model. The paper by Neufeld, Sawada, and Becker in this issue of the Proceedings (22), demonstrating protection of the optic nerveyretinal ganglion cells from the neurotoxic effects of chronically elevated IOP in a live animal model, by inhibition of the inducible isoform of nitric-oxide synthase (NOS-2), is the first to do so, and will likely be considered classic in years to come. The authors had previously demonstrated the presence of NOS-2 in astrocytes in the optic nerve head and lamina cribrosa of glaucomatous human eyes and chronically hyper-