Potential Neuroprotective Therapy for Glaucomatous Optic Neuropathy

Accumulating evidence points to the existence of a mechanism that may explain why glaucomatous neuropathy continues to progress even after its primary cause, e.g., high intraocular pressure, has been alleviated or attenuated. We suggest that such a mechanism involves processes collectively termed secondary degeneration, an inevitable outcome of acute injury of the central nervous system. Secondary degeneration refers to the spread of degeneration to apparently healthy neurons that escaped the primary insult, but are adjacent to the injured neurons and are thus exposed to the degenerative milieu that the latter create. Neuroprotection, i.e., protection of undamaged neurons from secondary degeneration, would therefore require that the extracellular elements associated with the degeneration be neutralized, balanced off, or inhibited. In seeking an experimental framework for testing treatment modalities for neuroprotection, we have developed an animal model in which a well-calibrated, reproducible, partial lesion is inflicted on the optic nerve of the adult rat. Using this model, the extent of the primary damage can be quantified and the secondary degeneration demonstrated and assessed. Damage inflicted directly on the optic nerve fibers inevitably leads to their degeneration and the eventual death of their cell bodies. Over time, neurons that initially escaped the injury undergo self-perpetuating secondary degeneration, the extent of which is a function of the severity of the primary insult. We suggest that a similar mechanism may underlie the propagation of damage seen in glaucoma at any given time after alleviation of the primary cause of the disease, and might explain why patients with severe pre-existing damage are much more likely to deteriorate even if their intraocular pressure is the same or lower than that of patients without visual loss at the time of diagnosis. The model can be used to screen compounds for their efficacy in protecting initially spared neurons from undergoing secondary degeneration, thereby achieving a better functional outcome. The findings obtained using this model support the attempt to develop neuroprotective therapy for glaucoma. Such therapy would need to be applied in combination with treatment (e.g., antihypertensive therapy) directed against the primary cause of the neuropathy. (Surv Ophthalmol42:367–372, 1998.