Biomedical Frontiers: Fall 1997, Vol.4, No.2
Nitric Oxide in Parkinson's

In the United States, some 750,000 to 1 million people suffer from the shaking, slowness of movement, and muscular rigidity of Parkinson's disease. Approximately 50,000 new cases of Parkinson's are diagnosed each year, with the disease touching such notables as Muhammed Ali, Attorney General Janet Reno, and Pope John Paul. Although the cause of Parkinson's disease remains unknown, current research suggests that nitric oxide plays a key role in the death of brain cells that occurs in the disease. At CPMC, researchers in the Movement Disorder Division are investigating possible treatments for Parkinson's--as well as for Alzheimer's disease and amyotrophic lateral sclerosis.

In 1992, a study by CPMC researchers suggested that free radicals have a significant role in damaging neurons in Parkinson's disease. This "oxidative stress" hypothesis concluded that the damage caused by free radicals slowly accumulates until it interferes with the functioning of a neuron, eventually killing it. However, the free radical that the study (in the Journal of Neuroscience, May 1992) identified--superoxide--was not highly reactive.

These results suggested that another agent was involved, and a study in the May 1996 Proceedings of the National Academy of Sciences found that this agent is nitric oxide. In the study, Dr. Serge Przedborski, lead author and assistant professor of neurology at Columbia, and colleagues blocked nitric oxide synthase (NOS), an enzyme needed to produce nitric oxide, to show that nitric oxide was involved.

The researchers used two methods to show the connection: In the first method, they injected MPTP (a chemical that induces Parkinson's-like damage in neurons) into mice whose synthesis of NOS had been inhibited by the chemical 7-nitroindazole. In the second method, the researchers administered MPTP into mice genetically engineered to lack the gene for NOS. In both cases, the results were the same: When NOS--and therefore nitric oxide--was blocked, the neuron-damaging abilities of MPTP were dampened.

The next step in the research will be to determine where nitric oxide is produced and to learn exactly how peroxynitrite (formed by nitric oxide and superoxide) causes damage.

The findings open up the possibility of treating several neurodegenerative disorders, including Parkinson's, Alzheimer's, and ALS, says Dr. Przedborski. "The initial mechanism may be different for various neurological disorders, but after that they may share a common pathway that ultimately leads to the death of the cell." The findings also offer the hope of a treatment that could slow the progression of these diseases. "With the current progress in neurodegenerative disorders, it's not realistic to believe that one day you will wake up and have a solution," says Dr. Przedborski. "But this study opens a beautiful way to intervene with what's going on. It may mean that people can still have a better life while research continues."