May 22, 2000 BLACKSBURG, Va., May 19, 2000 -- In a discovery that opens an important direction in the study of Parkinson's disease, Virginia Tech scientists have identified a compound in tobacco that inhibits an enzyme that breaks down key brain chemicals.
Parkinson's disease, a central nervous system disorder, causes the gradual deterioration of neurons in the section of the brain that controls movement. The brains of patients with Parkinson's disease typically have less of a neurotransmitter called dopamine. Studies have shown that smokers are 50 percent less likely to get Parkinson's than non-smokers, but no one has isolated a particular substance in tobacco that may be responsible for that phenomenon.
Neal Castagnoli, director, and Kay Castagnoli, senior research associate, at Virginia Tech's Harvey W. Peters Center in the chemistry department, located in the College of Arts and Sciences, conducted research that has lead to the isolation of a compound in tobacco that protects against the loss of dopamine in mice and thereby may protect against the development of Parkinson's Disease.
"Joanna Fowler, a scientist at Brookhaven National Laboratory in New York, found by positron emission tomography (PET) imaging that smokers' brains have 30 to 40 percent lower levels of monoamine oxidase (MAO)," Kay Castagnoli said. MAO normally breaks down neurotransmitters such as dopamine, serotonin, and norepinephrine. Since the Castagnolis had already been conducting research involving MAO and neuroprotection, "We thought about the connection," Castagnoli said.
They decided to examine if there was a substance in tobacco that inhibits MAO. Ashraf Khalil, a postdoctoral fellow in the group, was able to separate and characterize a compound called 2,3,6-trimethyl-1,4-napthoquinone, or TMN, which was also known to be present in tobacco smoke and proved to be an inhibitor of MAO.
Using mice, the Castagnolis first administered TMN and then a potent neurotoxin, MPTP, a contaminant that had been discovered in a street drug sold in the early 1980s. The drug was meant to mimic the effects of heroin, but addicts who took large doses of the synthetic heroin suffered severe Parkinsonian symptoms. Neal Castagnoli, then working at the University of California at San Francisco, was one of the scientists who determined what caused the brain to turn the contaminant into a toxin that caused many of its users to develop the Parkinsonian symptoms.
In the recent tobacco study, the Castagnolis discovered that TMN, found in tobacco smoke as well as leaves, did in fact interfere with MAO and protected the rodents against the toxic effects of the synthetic-heroin contaminant. Although this discovery opens up the possibility of new avenues of research, "No one should start smoking based on these results," Kay Castagnoli said, "and people should continue to stop smoking. There's no evidence that the benefits of smoking will ever outweigh the risks."
"The finding that smoking decreases the risk for Parkinson's disease raises the question of identifying the actual neuroprotective agent among the hundreds of compounds present in cigarette smoke," said Donato Di Monte, director of Basic Research at the Parkinson's Institute in Sunnyvale, Calif. The discovery in the Castagnolis' lab, he said, "provides a critical clue for the development of drugs that may directly reproduce the neuroprotective action of smoking without exposing people to its other harmful health effects."
The results of the Castagnolis' research, which has included a second study of mice that confirmed their initial findings, is an important step in the study of Parkinson's disease, he said. "This compound may be the one involved in neuroprotection, but there may be others that, by acting on the enzyme, may have neuroprotective effects." Also, Kay Castagnoli said, it could be possible, in pharmaceutical industries, that this basic structure could be used as a template for the development of neuroprotective compounds.
The research was presented at the American Chemical Society national meeting in March. This summer, the Castagnolis, along with Ashraf Khalil, will look for other neuroprotective agents in tobacco.
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