St. Louis, MO (8.19.99)- A new neuroprotective approach aimed at blocking
the synthesis of nitric oxide may offer the hope of new treatments for glaucoma,
a leading cause of blindness in the world.
The gradual vision loss seen with glaucoma is associated with a progressive
loss of retinal ganglion cells and axons leading to deterioration of the optic
nerve. Elevated intraocular pressure (IOP) has been a known risk factor for
glaucoma for at least a hundred years, and all current treatments aim to lower
IOP as a means to slow the progression of disease.
While
these pressure-lowering approaches have been shown to provide significant
benefit, none are curative. Some patients develop glaucoma in the absence
of elevated intraocular pressure, and others fail to show much improvement
even when the pressures are reduced. Researchers have only very recently begun
to explore the role that various neurochemicals play in the glaucoma disease
process. While the optic nerve is best known for carrying visual signals from
the retina to the brain, it also carries many other things including include
mRNA, proteins and amino acids.
Of particular interest are neurotrophins, peptides that interact with cell
surface receptors to moderate cell growth and stasis. As glaucoma develops,
the flow of neurotrophins to the retinal cells is impaired. This is part of
larger cascade of events associated with elevated IOP. Other factors include
ischemia, vascular dysfunction and the release of cytotoxins including glutamate.
The goal of neuroprotection therapy is to interrupt this process at one or
more stages.
New research conducted at the Washington University School of Medicine indicates
that excess nitric oxide(NO), a ubiquitous chemical in the human body, is
associated with increases in IOP and other signs of glaucoma in animal models.
They also determined that administering a drug that inhibits the synthesis
of NO appear to prevent or delay the progression of the disease.
"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. Using sophisticated staining techniques, we detected an enzyme
called inducible nitric oxide synthase in the optic nerve head tissue of patients
with glaucoma," said Arthur H. Neufeld, Ph.D., the Bernard Becker Research
Professor of Ophthalmology and Visual Sciences,Washington University School
of Medicine
This enzyme, NOS-2, can produce excessive amounts of nitric oxide. 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. 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," Neufeld said.
Next, 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.
"There were marked changes in the eyes of animals that did not receive
the drug. 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," Neufeld said.
Interestingly, 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. This indicates that
aminoguanidine did not lower the elevated pressure in these animals. That
is important because it means that lowering the pressure is not what protected
the retinal ganglion cells.
This encouraging finding gives 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 glaucoma, but no elevation
of IOP. Drugs that inhibit 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."
The significance of these findings may extend beyond glaucoma. Researchers
believe that similar processes may be involved in a number of neurodegenerative
and neurovascular diseases, including Parkinson's disease, Alzheimer's disease
and multiple sclerosis.
The research appears in the Aug. 17 1999 issue of the Proceedings of the
National Academy of Sciences.,
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