Neuropathy: The Good, Bad and Ugly of Nitric Oxide

Aaron Vinik MD, PhD, FCP, FACP.
Director of Strelitz Diabetes Research Institute

One man's meat may be another's poison! It was but a moment ago that Furchgott discovered that many important processes such as the ability to respond to pain (Nociception) and the capacity to open or dilate blood vessels was mediated by a tiny molecule called nitric oxide (NO). It is a little known fact that nitric oxide is a gas much like the laughing gas used by dentists to alleviate the pain inflicted by drilling into one's skull.

The discovery of nitric oxide as a pain reliever was so important that it merited a Nobel Prize. Meanwhile we, mere mortals in the Strelitz Diabetes Research Institute, were finding, much to our chagrin, a possible harmful effect of the gas. Who would believe us and take heed of our warnings?

For years we have known that persistently high blood glucose leads to the accumulation of reactive oxygen species (ROS) like hydrogen peroxide. Imagine having bleach circulating in your body! Well, that is what happens in poorly controlled diabetes.

To make matters worse, the ROS combines with NO to form a new compound called peroxynitrite. Now all the good effect of NO is neutralized, and worse still, heralds some really bad stuff. Peroxynitrite shuts off blood vessels, impairing the nutrient supply to the skin and to the nerves. It can also cause pain and foot ulceration, which may be the forerunner to amputations. There are 85,000 amputations in the United States each year; about one every 10 minutes. We believe that the conversion of nitric oxide to peroxynitrite is a major factor leading to amputations.

So have we, at the Strelitz Diabetes Institutes, been able to fight off this horrific event? Collaborating with Dr. Betsy Mason, an endocrinologist in our Clinical Care Institute, our scientists have shown that blocking the vasoconstrictors Angiotensin and Endothelin may be a step in the right direction. Dr. Gary Pittenger has shown in his laboratory that the drug Topiramate can restore the function of nerve cells, and cause the damaged C fibers to grow back in the skin.

Our clinical research verifies that in fact, nitrative stress can be reduced by Topiramate, as well as by using insulin sensitizers such as Pioglitazone.

The patients in these trials experience a remarkable improve-ment in nerve function determined by nerve function tests. What does this mean for the person with diabetes?

It translates to reduced pain, improved sensation and a decrease in the risk of foot ulceration. It should also prevent amputation and improve patients' quality of life (as determined by the SDI's Norfolk Quality of Life Tool, which has now been translated into 17 languages and is being used worldwide to determine the effects of different drugs in neuropathy).

The figure illustrates our new concepts on the mechanisms of pain and temperature perception: the role of these small sensory, C fiber nerves in skin and the role of nitric oxide causing dilation of the blood vessels. Peroxynitrite is formed in tissue by interaction between superoxide and nitric oxide. Elevated levels occur when there is increased formation of reactive oxygen species (the bad guy, like hydrogen peroxide!)
This happens in diabetes, atherosclerosis, and hypertension causing C fibers to disappear in diabetes and constricts rather than dilates blood vessels. This is definitely ugly! The studies carried out in our clinical research unit show that we now have agents that can combat these ill effects of diabetes. That's the good!

Abstracts on different aspects of this research have been submitted to the American Diabetes Association and American Endocrine societies for presentation at the national meetings in June, 2003.