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Parkinson's Inhibitor Fingered in Tobacco

SAN FRANCISCO--Smoking kills, it's true, but in at least one respect it appears to do a body good. Cigarette smokers are less likely to develop Parkinson's disease, a condition marked by the death of certain nerve cells that use the neurotransmitter dopamine, causing a progressive loss of muscle control. At last month's meeting of the American Chemical Society, a team of researchers described a molecule in cigarette smoke that may offer the protection.

Researchers suspect smokers have a decreased risk of Parkinson's because something in tobacco keeps dopamine levels near normal, even if a smoker does start losing dopamine-producing cells. Most likely, this mysterious bodyguard protects dopamine by inhibiting a brain enzyme called monoamine oxidase (MAO) that breaks down the neurotransmitter. Indeed, doctors have long used other MAO inhibitors to treat Parkinson's. And in 1996, brain scans by a team from Brookhaven National Laboratory in Upton, New York, revealed that smokers had as much as 40% less of the MAO enzyme in their brains than nonsmokers.

Kay and Neal Castagnoli, a husband and wife team of chemists at the Virginia Polytechnic Institute and State University in Blacksburg, set out to find the MAO-blocking compounds among thousands of other components in tobacco and tobacco smoke. They ground up tobacco leaves and tested representative samples in a test tube to see if they inhibited MAO. From the fraction containing the most potent MAO inhibitor, they isolated a chemical known as 2,3,6-trimethyl-1,4-naphthoquinone.

To find out whether this was a key MAO-inhibitor in cigarette smoke, Castagnoli's team examined mice in which dopamine-producing neurons were killed with a compound called MPTP that's converted to a toxin in the brain, causing symptoms much like Parkinson's disease. Without the naphthoquinone, dopamine levels in the mice given MPTP dropped 60% below normal. Yet when the mice were pretreated with naphthoquinone, dopamine levels fell only 40%. This suggests that naphthoquinone "is a good [MAO] inhibitor--not gangbusters, but a good inhibitor," Castagnoli says.

Napthoquinone had previously been found in tobacco smoke, but not linked to dopamine. The new finding suggests it might be protecting dopamine in smokers, but Castagnoli cautions that the team isn't sure about that yet. Still, the new work is exciting, says Janet Fowler, who led the Brookhaven studies. "It's really interesting to find one of these substances," Fowler says. And because the compound doesn't resemble any of the previously known inhibitors, it could give drug companies leads for new drugs to treat Parkinson's, she says.