Research by P&S neurologists shows that the COX-2 enzyme helps kill neurons in Parkinson's disease and that COX-2 inhibitors like Celebrex and Vioxx may be able to slow cell death in patients. The new study was published online April 17 on the Proceedings of the National Academy of Sciences Web site.
COX-2 enzymes are most familiar as promoters of inflammation in arthritis, but the enzymes produce inflammation in all damaged tissues, including the brain. Researchers now see inflammation as one of several processes in neurodegenerative diseases that intensify the initial illness. Slowing the additional processes may slow the progression of the disease. Epidemiological studies have already shown that non-steroidal anti-inflammatory drugs (a class to which COX-2 inhibitors belong) reduce the risk of developing Alzheimer's disease.
To see if COX-2 has a role in Parkinson's disease, Dr. Serge Przedborski, professor of neurology and pathology, and his postdoctoral researcher, Dr. Peter Teismann, first looked for the enzyme in postmortem brains from Parkinson's patients. They found higher levels of COX-2 in the substantia nigra's dopamine neurons from patients than in the same neurons from unaffected people. Dopamine neurons from the substantia nigra suffer the most damage during the course of Parkinson's disease.
The researchers also found the same high levels of COX-2 in the dopamine neurons of mice that develop a disease similar to Parkinson's. The mice develop many of the disease's symptomsincluding tremors and muscle rigidityafter injection of a chemical called MPTP. "No one believes Parkinson's is caused by an unknown exposure to MPTP," Dr. Przedborski says, "but it's believed they share a good portion of the cell death cascade, so if we study the MPTP model, we gain insight into why cells die in Parkinson's disease."
The mice data show that COX-2 is instrumental in the death of the substantia nigra's dopamine neurons. When the COX-2 enzyme gene was knocked out, or when the enzyme was blocked with a COX-2 inhibitor, more dopamine neurons were able to survive MPTP-induced damage. Rofecoxib, the COX-2 inhibitor, doubled the number of surviving neurons: 88 percent survived with the drug, while only 41 percent survived without the drug.
But Drs. Przedborski and Teismann were surprised to find that the COX-2 enzyme does not kill neurons through inflammation. Based on its role in promoting inflammation, the researchers expected COX-2 would activate the microglial cells that kill sick neurons. But this scenario predicts a reduction in activated glial cells when COX-2 is removed, and the researchers did not see any reduction in COX-2 knockouts or in mice given COX-2 inhibitors.
Instead, they found that the COX-2 enzyme may kill by oxidizing other molecules in the dopamine neurons. After mice were injected with MPTP, the researchers saw that dopamine was oxidized into dopamine-quinone, a molecule that can react with and damage other components of the cell. Excessive damage from dopamine-quinone may kill the cell. Drs. Przedborski and Teismann are currently investigating whether the molecules oxidized by COX-2 cause cell death or if COX-2 activates other pathways.
"Regardless of how COX-2 works in Parkinson's disease, the benefit we see in animal models with COX-2 inhibitors suggest the drugs could be useful in slowing the disease's progression in patients," Dr. Przedborski says. "The drugs are safe and they get into the brain reasonably well."
So far, no drugs have been shown to slow the degeneration of neurons in Parkinson's patients. One potential compound inhibits the JNK enzyme, which also promotes cell death after MPTP injection. Drs. Przedborski and Tiesmann found that the COX-2 inhibitors probably work on the same pathway as the JNK inhibitors, so that combining the two inhibitors would not increase the effectiveness of a single inhibitor. Columbia is currently involved in a multi-center trial testing the JNK inhibitor, and Dr. Przedborski says researchers are now planning new trials to test COX-2.
The research was supported by NINDS, U.S. Dept. of Defense, Lowenstein Foundation, Lillian Goldman Charitable Trust, Parkinson's Disease Foundation, Movement Disorders Association, and ALS Foundation. Dr. Teismann is supported by the German Research Foundation. Merck supplied the COX-2 inhibitor.