A Role for Glutamate in Glaucomatous Blindness

Research in our laboratory has focused on evidence for a new etiology for the blinding disease, glaucoma. Glaucoma is a leading cause of irreversible blindness both worldwide and in the United States, and affects up to ten million Americans. Although there are multiple etiologies for this disease, most are thought to involve an elevated eye (intraocular) pressure. The optic nerve damage (and blindness) seen in glaucoma has been attributed to an intolerably high level of intraocular pressure. As a result, for the past century the treatment of glaucoma has focused exclusively on pressure control. Pressure-mediated damage of the optic nerve has been variously explained by either a direct mechanical effect (a trauma hypothesis) or by compromise of the blood vessels (an ischemia hypothesis). These insults are thought to lead to loss of axons at the back of the eye, with the resulting death of retinal ganglion cell neurons (cells that are critical for the transmission of visual information, and for the human eye to see). For all forms of glaucoma, the only therapies – both medical and surgical – presently available are directed at decreasing the intraocular pressure. Unfortunately, this is not enough. In contrast to the treatment of systemic hypertension (high blood pressure), lowering the pressure in glaucoma is frequently not sufficient to prevent further damage. Even though the intraocular pressure can be brought into the normal range, visual field loss and blindness still frequently occur. It has been suggested that “intraocular pressure (is) simply one of several risk factors instead of an integral part of the definition of glaucoma.” Studies in the central nervous system over the past three decades, however, have found that both traumatic and ischemic neuronal injury – the two etiologies that have been proposed to explain the optic nerve loss in glaucoma – can be mediated by excessive levels of excitatory amino acids, especially glutamate. These prior investigations have predominantly explored the role of glutamate in stroke, trauma, epilepsy, and neurodegenerative disorders such as Huntington’s disease, amyotrophic lateral sclerosis, and AIDS dementia. Nevertheless, given that the neuron damaged in glaucoma- the retinal ganglion cell- is a bona-fide neuron of the central nervous system, we reasoned that perhaps excitatory amino acids might play a role in the retinal ganglion cell loss seen in glaucoma. This is further suggested by the fact that microscopically, eye damage caused by the ophthalmic injection of glutamate is almost identical to the damage caused by glaucoma. We have demonstrated an elevated level of glutamate in the vitreous of glaucoma patients. Glutamate, which can be neurotoxic to retinal ganglion cells through its action at N~methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor, might therefore contribute directly to the blindness seen in glaucoma. The presence of glutamate in the vitreous of glaucoma patients appears to develop even if the intraocular pressure is well controlled. Accordingly, even if a patient religiously complies with his or her medical therapy to lower the eye pressure, visual loss might still occur because nothing has been done to block the toxicity caused by glutamate. Blockade of glutamate toxicity in the eye might prevent glaucomatous loss, and preserve the patient’s vision. We have recently discovered additional information that strengthens our hypothesis that glutamate is implicated in glaucomatous blindness. As glaucoma damages the optic nerve at the back of the eye, it first damages the larger retinal ganglion cells, and only secondarily destroys the smaller ones. In our experiments, glutamate likewise damages larger cells first, and, only at higher concentrations, kills the smaller retinal ganglion cells – and this is true not only in the tissue culture dish, but also in the intact eyes of experimental animals. This is further confirmation that glutamate may play a role in glaucomatous blindness, and suggests that drugs that block glutamate toxicity may be useful in controlling this disease. Our future work will be directed at exploring – in an animal model first – whether agents that block glutamate toxicity can also block glaucomatous damage. If this is in fact the case, it may be possible to attempt clinical trials in patients with this devastating eye disease.