BackgroundFor the past 30 years, neuroscientists have sought to use neuroprotection -- the therapeutic paradigm directed at slowing or preventing death of diseased neuronal tissue to preserve and maintain physiologic function -- to treat central nervous system diseases. But success has been fleeting: Numerous pharmacologic neuroprotective agents that were initially investigated in the laboratory have almost invariably failed to translate to the clinic. Indeed, only memantine for Alzheimer disease[1] and riluzole for amyotrophic lateral sclerosis[2] have demonstrated improved outcomes. In the case of glaucoma, research into neuroprotection for glaucoma has suffered a number of setbacks. Still, preliminary findings continue to suggest that there may be a role for neuroprotection in the treatment of glaucoma, and research is ongoing.
Rationale for Neuroprotection to Treat GlaucomaGlaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder.[3] It is characterized by the acquired death of retina ganglion cells (RGC) and loss of their axons as well as optic nerve atrophy and loss of neurons in the lateral geniculate nucleus and the visual cortex. In primary open-angle glaucoma, intraocular pressure (IOP) is the most important risk factor for glaucoma onset and progression. It is currently the only risk factor amenable to modification by the clinician. However, there are limitations to treating IOP exclusively, including:
•Most patients with elevated IOP never develop glaucoma;
•Many glaucoma patients do not have a statically elevated pressure (ie, low-tension glaucoma); and
•There are many patients who continue to progress with controlled low IOP.
These observations suggest that IOP-independent mechanisms contribute to disease onset and progression, and indeed, in vitro studies of RGC and animal models of optic nerve injury and elevated IOP have examined such mechanisms, particularly RGC death by apoptosis (a form of cell suicide in which the cell actively participates in its own demise).[4,5] RGCs undergo apoptosis when they are disconnected from their axon or when their axon is disconnected from its intracranial target. The steps involved in apoptosis of RGCs occur over hours or days, which offers a window of opportunity in which neuroprotective agents might work.
Ongoing Research Into Neuroprotection for GlaucomaThe randomized clinical trial is the gold standard by which neuroprotection will ultimately be assessed in glaucoma. To date, no randomized clinical trial has demonstrated a clear benefit for neuroprotection, although in vitro cell models and in vivo models of optic nerve injury have suggested a benefit.[6,7] There are a number of potential reasons for these discrepancies, including:
•An animal model cannot properly simulate human disease;
•The pathophysiology of human disease is intrinsically different from that in animals; and
•There is more variability in patients than in laboratory animals.
Furthermore, a RGC culture cannot reflect the complicated pathophysiology of the human disease. Laboratory glaucoma models induce elevated IOP in young healthy homogeneous animals with early open-label administration of the test agent; assessment of neuroprotection is most commonly performed by postmortem counting of RGC. In contrast, patients with glaucoma are heterogeneous, can be on many ocular and systemic medications, have comorbidities, and may not have control of physiologic parameters. In addition, the stage of the human disease process and the intraocular concentration of the intervention are unknown. However, despite these difficulties, research into neuroprotection is progressing. A few of the main avenues of exploration are discussed below.
Alpha-2-adrenergic AgonistsLaboratory studies have demonstrated that alpha-2-adrenergic agonists are neuroprotective in experimental cases of optic nerve injury, models of glaucoma, ischemia-induced injury, and photoreceptor degeneration.[8] In 1993, animal models of the alpha-2-adrenergic agonist dexmedetomidine showed it to be neuroprotective against focal cerebral ischemia.[9] With that background, brimonidine tartrate, a highly selective alpha-2-adrenergic agonist IOP-lowering agent,[10,11] was investigated for possible neuroprotective properties. Potential mechanisms for its neuroprotective effects included up-regulation of brain-derived neurotrophic factor in RGCs and the retina, activation of cell-survival signaling pathways and anti-apoptotic genes, and modulation of N-methyl-D-aspartate (NMDA) receptor function.[12-15] Animal and human studies have demonstrated the presence of alpha-2 receptors in the retina.[14,16,17] And systemic administration of brimonidine in rat models with ocular hypertension protected RGCs following partial crush injury to the rat optic nerve.[12,18-20] Still, clinical trials in nonglaucomatous diseases, such as nonarteritic anterior ischemic optic neuropathy, Leber hereditary optic neuropathy, and retinal dystrophies, have failed to show treatment benefit with alpha-2 agonist use.[8] Randomized, clinical trials are still needed to better understand what if any neuroprotective effect alpha-2-adrenergic agonists may have in eyes with glaucoma.
One study that may help elucidate the effects of brimonidine is the completed Low-pressure Glaucoma Treatment Study (LoGTS), a double-masked, randomized, multicenter clinical trial comparing the efficacy of medications with equal IOP-lowering efficacy (bilateral twice daily topical monotherapy with brimonidine tartrate 0.2% vs timolol maleate 0.5%[11,21]) in preventing or delaying visual field progression in patients with low-pressure (normal-tension) glaucoma. Although any separation between normal and abnormally elevated IOP is intrinsically arbitrary, population-based studies have demonstrated that low-pressure glaucoma represents 20% to 39% of patients with open-angle glaucoma in the United States and Europe.[22-24]
The LoGTS[25] includes 190 patients with untreated IOP of 21 mm Hg or lower, open iridocorneal angles, at least 2 reproducible visual fields with glaucomatous defects in at least 1 eye on automated perimetry with the location of the field defect consistent with the photographic appearance of the optic nerve head, and age 30 years or older. The main outcome measure is field progression, defined as the same 3 or more points with a negative slope equal or greater than -1 db/year at the P < 5% level, on 3 consecutive tests assessed by pointwise linear regression (PLR). Secondary outcome measures are field progression based on glaucoma change probability maps of pattern deviation and the 3-omitting method for PLR. This clinical trial on a selected glaucoma subset is completed and the outcome is under review.
Memantine Glaucoma Clinical TrialExcitotoxicity through excessive glutamate and stimulation of its receptors, including the NMDA receptor, is reported to be important in a number of neurodegenerative diseases.[26] Elevated levels of glutamate were reported in the vitreous in humans and monkeys with glaucoma.[27] Memantine, an NMDA open-channel receptor antagonist, was shown to have neuroprotective properties in a monkey glaucoma model,[28,29] and a randomized trial was undertaken. The trial -- which included all types of open-angle and chronic angle-closure post-iris surgery patients, including those with prior filtration surgery -- investigated 2 oral doses of memantine vs an arm of oral placebo in glaucoma patients with controlled IOP. The treating physician had total control of patient management, including IOP-lowering medications, to perform angle laser or filtration surgery, or to perform cataract removal. Each of the 2 parallel arms had 1100 patients from sites worldwide that were followed for at least 4 years. The main outcome measure was visual field progression from full threshold examinations performed every 6 months.
Unfortunately, the trial results have not been published. Neither of the parallel arms met the primary outcome measure according to a press release[30]; memantine did not show benefit in preserving visual function. Despite this setback, it is too early to abandon memantine or the neuroprotective approach. The press release indicated that memantine demonstrated a statistically significant benefit from the high dose compared with the low dose. Reports from the trial should produce important information related to glaucoma management as well as possible insights into the design of future neuroprotective glaucoma trials. It is possible that the results were at least partially affected by the fact that glaucoma subjects in this trial had diverse types of glaucoma and IOP-lowering treatments at baseline as well as during the study. Also, the assessment of visual field progression used standards from the 1990s.
Nerve Growth FactorGrowth factors are a heterogeneous group of endogenous proteins secreted by the body to control the growth, division, maturation, and proliferation of various cells and tissues. Nerve growth factor (NGF) was discovered by Rita Levi-Montalcini and Stanley Cohen in the late 1950s from salivary gland isolates to induce the differentiation and survival of particular target neurons. Like the majority of growth factors, with the exception of erythropoietin and colony-stimulating factor for anemia treatment, NGF has not evolved into a proven and approved clinical application.
Lambiase and colleagues[31] studied the intravitreal administration of NGF in experimental models of RGC degeneration and found the protein to be effective. An apparently unique feature of NGF was its ability to penetrate to the retina when administered topically, in spite of its being a large protein with a molecular weight of 30,000. In a recent publication, Lambiase and colleagues[32] reported survival of RGC in a rat glaucoma model receiving topical NGF 4 times daily for 7 weeks. They also treated 3 patients with advanced glaucoma with a murine topical NGF for 3 months and reported improvement in visual acuity, contrast sensitivity, perimetry, and electrophysiological functions. It should be stressed that no conclusions may be drawn from this small, short-term, open-label clinical study.
Considerations for Future Approaches to Glaucoma Neuroprotection Trials
As neuroprotection research moves forward in glaucoma, there are a number of approaches that can be taken in new trials that may help to better assess the feasibility of this approach. It will be important to ensure that randomized trials include a well-defined and homogenous glaucoma population. This should include patients with one defined glaucoma diagnosis, baseline moderate disease stage (level of optic nerve and visual field damage), IOP limits, and glaucoma treatments, as well as outcome measures that include the currently available visual field and structure (optic nerve and retinal nerve fiber) measurements. Evolving imaging methods should also be examined and if possible incorporated into studies. These may include the use of noninvasive in vivo real-time and reproducible imaging of RGC potentially through fluorescently labeled annexin V and fluorescent ophthalmoscopy[33,34] and magnetic resonance imaging (MRI) to, among other uses, visualize the lateral geniculate nucleus and assess shrinkage of visual structures along the geniculo-cortical pathway.[35,36] Finally, other strategies may include the use of prolonged methods of drug delivery, such as sub-Tenons and intraocular injection devices. As new trials are designed and implemented, a better understanding of the potential for neuroprotection in glaucoma should evolve.
Refrence:
MedscapeCME Ophthalmology/Neuroprotection and Glaucoma/Theodore Krupin, MD/01/29/2010
