Study suggests potential new approach to glaucoma therapy

August 17, 1999

St. Louis, Aug. 17, 1999 -- Investigators at Washington University School of Medicine in St. Louis believe they have identified the basis for a new way to treat glaucoma, the second-leading cause of irreversible vision loss in the United States.

In the Aug. 17 issue of Proceedings of the National Academy of Sciences, the investigators report on experiments involving an animal model of glaucoma. Working in rats with elevated eye pressure, they were able to prevent loss of retinal ganglion cells by inhibiting the action of an enzyme that makes nitric oxide.

"Having seen reports on nerve damage caused by excessive nitric oxide, we decided to look for evidence of high levels of nitric oxide in human eyes with glaucoma," said lead author Arthur H. Neufeld, Ph.D., the Bernard Becker Research Professor of Ophthalmology and Visual Sciences. "Using sophisticated staining techniques, we detected an enzyme called inducible nitric oxide synthase in the optic nerve head tissue of patients with glaucoma."

This enzyme -- NOS-2 -- can produce excessive amounts of nitric oxide, and Neufeld and colleagues regarded its presence as evidence that nitric oxide might be involved with the ganglion cell damage seen in glaucoma. To explore that idea, they set out to determine whether NOS-2 was causing the damage in retinal cells or appearing as a byproduct of that damage.

"We adopted an animal model of glaucoma that raises pressure levels in the eyes of rats," Neufeld said. "And we found that, as in humans, the eyes of rats with elevated pressure lost retinal ganglion cells and that the tissue also contained elevated levels of NOS-2."

For the last century, most medical and surgical therapies for glaucoma have attempted to lower pressure in the eye, aiming to prevent or delay damage to ganglion cells and preserve good vision. "But we have many clinical situations where we can't get the pressure low enough to avoid damage," said Bernard Becker, M.D., professor emeritus and former head of the Department of Ophthalmology and Visual Sciences. "In spite of the drugs we have, in spite of surgery, in spite of everything we try to do, the patient continues to lose vision."

Inhibiting NOS-2 may provide a new option. The investigators put a drug called aminoguanidine into the drinking water of rats with elevated eye pressure. Other rats did not get the drug. After six months, the researchers found that the untreated rats lost 36 percent of their retinal ganglion cells in the eyes with elevated intraocular pressure. Those who received aminoguanidine lost less than 10 percent of their retinal ganglion cells in spite of continued elevated intraocular pressure.

"As the paper reports, there were marked changes in the eyes of animals that did not receive the drug," Neufeld said. "But we didn't seen that type of cell loss in animals that were treated with aminoguanidine. Statistically, the retinal ganglion cell loss was not any different than in the controls."

Processes from retinal ganglion cells leave the eye through a structure called the optic disc, and ophthalmologists keep a close watch on the optic disc in glaucoma patients. In this study, Becker did the same thing with the rats.

"Once a month, we looked into the animal eyes through an ophthalmoscope," he explained. "Patients with glaucoma develop 'cupping' of the disc -- a bowing back and atrophy of that structure. These rats also were developing this cupping of the optic disc, but in those treated with aminoguanidine, no cupping occurred."

Although the rats treated with aminoguanidine had less damage in the retina and the optic nerve, their intraocular pressure was no different than in animals that did not receive the drug. "That means aminoguanidine did not lower the elevated pressure in these animals," Neufeld said. "That is important because it means that lowering the pressure is not what protected the retinal ganglion cells."

That fact gives the researchers hope that it may be possible to treat patients whose glaucoma does not respond to pressure-lowering drugs or surgery, as well as a subset of patients who have what doctors call normal-pressure glaucoma. The hope is inhibitors of NOS-2 might preserve vision in those patients who don't respond to current therapies and also could be used along with drugs that lower intraocular pressure.

"The emerging concept of using drugs to protect nerve cells is being aggressively pursued across the country," said Carl Kupfer, M.D., director of the National Eye Institute, part of the National Institutes of Health, the federal agency that helped fund the study. "New approaches to treating glaucoma are welcome, and this work will be followed closely by other glaucoma researchers."

Robert Ritch , M.D., agrees. He is chairman of the scientific advisory board of The Glaucoma Foundation, which also helped fund this project. "We're getting closer to finding the answers," Ritch said. "Although the current investigations do not yet translate into clinical use, this is the sort of breakthrough research that could eventually lead to a stemming of vision loss from glaucoma."

In an accompanying commentary article, Paul L. Kaufman. M.D., professor and Director of Glaucoma Services at the University of Wisconsin-Madison, said the paper "will likely be considered a classic in years to come" and that the study's conclusions may contribute to more than finding better treatments for glaucoma. "The significance of their findings may go far beyond glaucoma, with broad pathophysiologic and therapeutic implications for neurodegenerative and neurovascular diseases in general," Kaufman wrote.

For now, however, the research is focusing purely on glaucoma. In future animal studies, Neufeld and Becker will test other drugs that inhibit production of NOS-2. If their work progresses, human trials may follow.

This research was supported by grants from the National Eye Institute and the Glaucoma Foundation.
-end-
Neufeld AH, Sawada A, Becker B. Inhibition of Nitric Oxide Synthase-2 by Aminoguanidine Provides Neuroprotection of Retinal Ganglion Cells in a Rat Model of Chronic Glaucoma. Proceedings of the National Academy of Sciences, vol. 96 (17), pp 9944-9948, Aug. 17, 1999.

Copies of the paper are available from the PNAS news office, 202-334-2138, or email pnasnews@nas.edu.

Washington University School of Medicine

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