Sci. Aging Knowl. Environ., 16 April 2003
Vol. 2003, Issue 15, p. nw57
[DOI: 10.1126/sageke.2003.15.nw57]

NOTEWORTHY ARTICLES

Parkinson's Shake-Up

Common anti-inflammatory drugs might spare brain cells of patients through unanticipated mechanism

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/15/nw57

Key Words: striatum • Lewy bodies • prostaglandin E2Ptgs2

Drugs to stall Parkinson's disease might already be on pharmacy shelves, according to a new study. A compound that stymies an inflammatory enzyme called COX-2 limits brain damage in mice with an artificial form of the disease. By tying neurodegeneration to COX-2, the research reveals similarities between Parkinson's disease, Alzheimer's disease, and other brain illnesses, but it suggests that the enzyme kills cells in an unanticipated way.

In Parkinson's disease (PD), cells that produce the neurotransmitter dopamine and dwell in the brain region called the substantia nigra die in droves (see Andersen Review). Drugs and surgery can ameliorate symptoms but don't slow progression of the disease (see Parkinson's Disease Case Study). Recognition that inflammation marks some neurodegenerative diseases might open new treatment possibilities. Swarms of activated immune cells show up in brain autopsies of PD patients, and drugs that block the inflammation-spurring enzyme COX-2 diminish the risk of AD (see "More Than a Painkiller"). Neurologist Serge Przedborski of Columbia University in New York City and colleagues suspected that COX-2 might spark PD's cellular slaughter.

To find out, they measured amounts of the enzyme in substantia nigra cells from PD patients and from mice dosed with MPTP, a compound that triggers a PD-like condition by poisoning cells in this brain region. Both types of neurons carried far more COX-2 than normal cells did. To determine whether COX-2 slays cells, the team disabled the enzyme in two ways. Mice engineered to lack the gene for COX-2 lost less than half as many cells as did control rodents when zapped with MPTP. Feeding normal mice rofecoxib, a drug that inhibits COX-2, also reduced neuron die-off. Because prior studies linked PD to inflammation, the researchers hypothesized that COX-2 kills neurons by triggering them to release chemicals that stimulate immune cells, which in turn emit toxic compounds. However, neither rofecoxib treatment nor COX-2 gene deletion prevented activation of immune cells, suggesting that COX-2 doesn't encourage inflammation. The enzyme stimulates production of reactive oxygen species, destructive compounds that damage key molecules, and Przedborski and colleagues found that rofecoxib reduced the amount of dopamine wounded by oxidants. The experiments suggest that in mice and possibly in humans, COX-2 wreaks havoc by unleashing reactive oxygen species, not by firing up inflammation, says Przedborski.

The paper "points to a potential therapy that is relatively nontoxic," says neurologist David Fink of the University of Pittsburgh. Millions of people already take aspirin, Vioxx, and other COX-2 blockers to battle rheumatoid arthritis and other inflammatory diseases. If these drugs could slow the progression of PD, "that would be a big step," Fink says. However, neuroscientist Ole Isacson of Harvard Medical School points out that the researchers injected MPTP on only one day--a brief dose that rapidly sickens and kills neurons in the substantia nigra. Human patients lose cells over many years, so the mechanisms of cell death in PD are different, he notes. Still, the two scientists agree that COX-2's role deserves further research. If the work pans out, delaying PD could be as easy as a trip to the local drugstore.

--Mitch Leslie


April 16, 2003
  1. P. Teismann et al., Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc. Natl. Acad. Sci. U.S.A., April 2003 [e-pub ahead of print]. [Abstract] [Full Text] [Links will work when the article goes online.]
Citation: M. Leslie, Parkinson's Shake-Up. Sci. SAGE KE 2003, nw57 (16 April 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/15/nw57








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