History of neuroprotection and rationale as a therapy for glaucoma.

Neuroprotection is any therapy that prevents, retards, or reverses apoptosis-associated neuronal cell death resulting from primary neuronal lesions. Although more than 500 products have been investigated for neuroprotective effects, there has been a low rate of success in human trials. Reasons include failure of the animal model to simulate human disease, human disease variability, brain size and development differences, variations in the ratio of axonal to neuronal damage, and lack of efficacy of the compound under study. Other reasons include narrow drug therapeutic index, drug molecular size, the small treatment window after cellular injury, multiple comorbidities of test subjects causing recruitment and statistical challenges, and insufficiently valid and reliable end points. Glaucoma is a neurodegenerative disease for which the neuropathic pathology has been studied since 1972. There have been recent significant advances in understanding the mechanisms for death of retinal neurons, and numerous agents are under development. Memantine, currently approved for Alzheimer's disease and in phase 3 trials for glaucoma progression, is one of the most studied neuroprotectants in glaucoma. Therapies that prevent death of the retinal ganglion cell (neuroprotection), its axon (axoprotection), or both, theoretically should be useful in treating glaucoma.