Synthetic drug slows glaucoma in rats.

In glaucoma, pressure buildup in the eyeball can lead to blindness by disabling the nerves in the back of the eye that send images to the brain. The pressure causes excessive production of nitric oxide, which can assume a toxic form that kills the retinal cells that carry information through the optic nerve.

By neutralizing an enzyme known to spur nitric oxide production, researchers studying rats at Washington University in St. Louis are now able to hold such nerve damage at bay---even if pressure in the eye remains high.

Eye pressure rises when normal fluid discharge from the eye becomes blocked. Pressure-reducing medication such as beta-blockers can ease this condition in many glaucoma patients, but some forms of the disease resist these drugs and continue to destroy nerve cells, which don't regenerate.

The scientists cauterized blood vessels to induce high pressure in one eye of each of 16 rats. Half the rats then received aminoguanidine in their drinking water. This synthetic drug inactivates nitric oxide synthase-2, or NOS-2, an enzyme that responds to the tissue damage by launching--for reasons that are still unknown--a flurry of nitric oxide production.

Over 6 months, nerve cells called ganglion cells remained constant in each rat's healthy eye. The unmedicated rats, however, lost an average of 36 percent of the ganglion cells in the retinas of the eyes with glaucoma. Those getting aminoguanidine did not lose significant numbers of these cells, says study coauthor Arthur H. Neufeld, an ophthalmic pharmacologist.

Abnormally high pressure persisted in the cauterized eyes of both groups of rats. "We showed that despite the pressure, we were still able to protect the ocular ganglion cells," says Neufeld. The findings appear in the Aug. 17 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

Monthly examinations of the rats revealed cupping of the optic disk at the back of the untreated eyes with glaucoma. Such malformation serves as a sign of glaucoma in people.

Since a rat's life span is only a few years, the 6 months needed for significant nerve damage to accumulate parallels the period of years over which the common chronic form of glaucoma develops in people, Neufeld says.

In this study, the scientists were able "to find a way to really protect the optic nerve, not just lower eye pressure," says Paul L. Kaufman, an ophthalmologist at the University of Wisconsin-Madison. Because this study opens the door to treatments aimed at inhibiting the NOS-2 enzyme, "it will likely be considered a classic in years to come," he says.

Excess nitric oxide begets a toxic substance called peroxynitrite. Neufeld hypothesizes that curbing nitric oxide production limits peroxynitrite concentrations. The compound is thought to degrade nerve cells and possibly induce apoptosis, or programmed cell death.

Whatever the precise mechanism behind the nerve damage, the study shows that aminoguanidine protects against it in the rat model, Neufeld says. Aminoguanidine was originally developed and tested, without much success, as a treatment for diabetes. Its prospects as a glaucoma drug seem brighter.

While lowering eye pressure eases glaucoma in many cases, too much pressure reduction can do damage. As a result, the enzyme-blocking approach for glaucoma "is very much welcomed," says Carl Kupfer, director of the National Eye Institute in Bethesda, Md.