Neuroprotection: is it already applicable to glaucoma therapy?

Neuroprotection: is it already applicable to glaucoma therapy?

Ritch, Robert MD

Abbreviations:IOP intraocular pressure, NMDA N-methyl-D-aspartate

Neuroprotection is an area of rapidly expanding research and has been a focus of numerous conferences and symposia, notwithstanding the absence to date of any proven clinically effective neuroprotective agent for the treatment of glaucoma [1-4••]. This interest is due to the fact that neuroprotection represents a new avenue of therapy for a frustrating disease that often progresses despite lowering of intraocular pressure (IOP) to acceptable or normal levels. As neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems-including trauma, epilepsy, stroke, Huntington disease, amyotrophic lateral sclerosis, and AIDS dementia-it is logical that their use in the treatment of glaucoma should be explored [5••].

Glaucoma is ultimately a neurologic disease. It is a progressive optic neuropathy that represents the final common pathway of a number of different disorders affecting the eye. Most, but not all, of these are associated with elevated IOP, which is the most important known risk factor for optic nerve damage but is still only a risk factor and not the disease itself.

Non-IOP-independent mechanisms of glaucomatous damage are not confined to normal-tension glaucoma but can be operative in any patient, although they predominate when glaucomatous damage occurs at the lower end of the pressure spectrum. The higher the IOP at which glaucomatous damage occurs, the greater the IOP-dependent damage. The lower the IOP at which damage progresses, the greater the contribution of non-IOP-dependent risk factors. However, there is no magic number at which one becomes operative and the other inoperative.

In the past decade, elucidation of non-IOP-dependent risk factors for glaucomatous damage has become an area of increasingly active investigation. These risk factors include systemic hypotension, including positional or nocturnal hypotension [6-9]; cardiovascular disease [10-13]; vasospasm (migraine, Raynaud disease) [14-20]; defective vascular autoregulation [18,21-23]; sleep apnea [24]; autoimmune disease [25-27]; hemorheologic abnormalities [11,28]; and cerebral microvascular ischemia [29]. For the most part, no specific treatments for these risk factors, when they can be identified in a particular patient (which is currently rare), are yet available. Therefore, a drug that would protect the optic nerve from damage from whatever cause, whether it be elevated IOP, ischemia, or excitotoxicity, would be a welcome addition to our armamentarium.

The newest approach to glaucoma centers around treatment targeted toward the preservation of retinal ganglion cells and other components of the optic nerve. The concept of secondary degeneration is based on the finding that neuronal damage in the central nervous system may progress even when the primary cause of damage is alleviated. Neuronal death may be viewed as occurring in three steps: 1) axonal injury, 2) death of the injured neuron, and 3) injury and death of previously intact neurons through secondary degeneration. Neuroprotection refers to the preservation of those neurons that initially were undamaged or only marginally damaged but are at risk from toxic stimuli released by damaged cells. Neural rescue refers to the restoration of viability to neurons that are already damaged. Neuroprotection is useful even when the exact cause of a disorder is undefined, as the therapy occurs at the level of the dying cells and not at the level of initial injury [30].

It has been proposed that the processes by which neurons die in various diseases are fundamentally the same but vary in cause. Osborne et al.[31] have suggested that neuroprotectants are more likely to benefit a patient in diseases in which the neurons die slowly, as in glaucoma, than in a disease in which the death of a set of neurons is rapid. Progressive loss of nerve cells represents a general pattern of damage in neurologic diseases, so that, regardless of the primary cause of neuronal cell death, damage spreads beyond directly injured neurons to adjacent neurons that escape the primary lesion [32-34]. Whether the primary lesion is caused by hypoxia-ischemia, stroke, seizures, trauma, or degenerative disease, changes in the extracellular environment include alterations in ion concentrations, an increase in free radicals, neurotransmitter release, depletion of growth factors, and immune system involvement [32,35]. These changes lead to apoptosis [36-39].

It has been hypothesized that an excessive release of the excitatory amino acid glutamate in the retina may contribute significantly to cell death [40-42]. Glutamate is an important neurotransmitter in the retina [43] and is present in high concentration in retinal ganglion cells. However, when excess glutamate is released into the surrounding medium, it is thought to activate a toxic response in adjacent cells. Excitotoxicity is mediated by overstimulation of the N-methyl-D-aspartate (NMDA) receptor, which in turn leads to excessive levels of intracellular calcium [44,45]. This in turn leads to activation of enzyme nitric oxide synthase, excess free radical accumulation, lipid peroxidation, mitochondrial dysfunction, activation of catabolic enzymes (such as nucleases and proteases), and cell death. Larger ganglion cells are particularly susceptible to glutamate toxicity [46]. Elevated glutamate levels have been found in the vitreous of patients with glaucoma, with higher levels in patients with worse disease [47]. In monkeys with untreated laser-induced glaucoma, the concentration of glutamate in the posterior vitreous was seven times that of normal concentration [48]. It is still uncertain whether the high vitreous levels of glutamate are a cause or result of damage, or both, but such concentrations are sufficient to cause progressive death of ganglion cells in a rat model of chronic glutamate exposure [49].

Ways to modulate the cellular response to glutamate include drugs that either block glutamate release or interact with the NMDA receptor to block either the interaction of the receptor and glutamate or affect the channel directly. NMDA antagonists can inhibit overstimulation of the NMDA receptor, which may then provide neuroprotection by preventing excessive calcium influx. One NMDA antagonist presently undergoing testing in a prospective, randomized, placebo-controlled multi-institutional study in the United States is memantine, long available in Germany (Akatinol Memantine, Merz and Company) for use in other neurologic disorders. Memantine effectively blocks the excitotoxic response of retinal ganglion cells both in culture and in vivo[49,50]. In a rat model of retinal ischemia created by elevating IOP to 120 mmHg, memantine reduced ganglion cell loss when given systemically before or within 30 minutes of retinal ischemia [51•]. Memantine was effective in ameliorating symptoms of Parkinson disease in a prospective double-masked study [52].

Another exciting potential approach to neuroprotection was published in a highly publicized report by Neufeld et al.[53••]. Having noted previously that the inducible form of nitric oxide synthase (NOS-2) was present in optic nerve head astrocytes from human glaucomatous eyes [54] and in rat eyes with chronic elevation of IOP [55], but not in normal eyes, they examined the use of oral aminoguanidine, an inhibitor of NOS-2, for its effect in preventing glaucomatous cupping in a rat model created by cautery of three episcleral vessels [55]. After 6 months of treatment, the optic nerve heads of the untreated animals had pallor and cupping, whereas those of the aminoguanidine-treated animals appeared normal. In histologic specimens, the untreated eyes lost a mean of 36% of their retinal ganglion cells, whereas those in the treated group lost less than 10%. The authors noted that aminoguanidine has been used in human clinical trials for complications related to diabetes.

What can be used now? A number of neuroprotective agents have been approved by the Food and Drug Administration in the United States for use in various neurologic disorders. A review of these is beyond the scope of this chapter. In the absence of any controlled trials examining the effect of these drugs in glaucoma, there are a few compounds easily available, some of them over-the-counter, which, hypothetically at least, may provide some benefit.