University of Toronto researchers have discovered a new mechanism for the neurodegenerative effects of amphetamines. These drugs are converted in the brain into free radicals, highly reactive molecules that cause neurodegenerative brain damage and whose effects manifest and linger long after the amphetamine has left the body.
"The question of whether amphetamines like ecstasy (MDMA) or methamphetamine (METH) cause neurodegeneration in humans is one of the most controversial areas in science today," says Professor Peter Wells of the Leslie Dan Faculty of Pharmacy, lead author of the study that appears in the April issue of the Journal of the Federation of American Societies for Experimental Biology (FASEB Journal). "The short-term effects of these drugs -- hypothermia, electrolyte imbalances and an elevated risk of heart attack -- are well understood, but not their long-term consequences."
Wells and doctoral students Winnie Jeng, Annmarie Ramkissoon and Toufan Parman theorized that prostaglandin H synthase (PHS) -- an enzyme that synthesizes a range of hormones throughout mammalian life -- is the catalyst that transforms amphetamines into free radical products that react with oxygen in the body to enhance the formation of highly toxic reactive oxygen species. These toxic forms of oxygen are implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's because of the increased oxidative stress they place on the body, resulting in irreversible damage to DNA, proteins and lipid membranes. Organs such as the brain, which lack abundant antioxidant protection, are particularly vulnerable to oxidative stress.
To approximate an acute human exposure, the researchers administered four doses of either MDA (the major metabolite of ecstasy) or METH at two-hour intervals to young adult mice. In the case of MDA, before the first drug injection an additional group of mice was given a single dose of aspirin (acetylsalicylic acid), which is known to inhibit PHS and block its ability to convert drugs to free radical products. Over a six-month period, following the single day's treatment of MDA or METH, the mice were observed and had their motor co-ordination tested by walking on a rotating rod. Normally, mice balance easily on the rods for extended periods. Within two weeks of the last treatment, all the mice given MDA or METH without aspirin had trouble with this task and remained disabled for at least six months. These mice also exhibited enhanced molecular damage to the DNA in their brains and a loss of nerve terminals that remained for at least one week after exposure to MDA or METH. The mice pretreated with aspirin had less molecular damage to their DNA and fewer motor disabilities, suggesting that the neurodegenerative effects of MDA are dependent upon its conversion by PHS into a reactive free radical product.
"Our findings reveal how exquisitely susceptible brains are to this kind of damage, at least in mice," Wells says. "The long-term negative effects in the mice treated with MDA or METH all resulted from a single day's dosage that approximated the higher range of human exposures."
Although the team's findings cannot be extrapolated to humans without further study, Wells believes they do suggest a novel mechanism through which amphetamines may contribute to neurodegeneration.
"Our hypothesis about PHS-catalyzed conversation may also be relevant to the neurodegenerative risks associated with aging," he says. "Preliminary results from other studies suggest that PHS may convert other compounds in our brains into free radicals, and there is some evidence in the clinical literature that suggests patients who take high doses of PHS-inhibiting drugs such as aspirin may experience less neurodegeneration. The potential of substances like aspirin to prevent neurodegenerative damage merits more examination, particularly among people who take it chronically for pain."
This study was funded by the Canadian Institutes of Health Research, with support from the National Institute on Drug Abuse (U.S.A) and Health Canada's Healthy Environments and Consumer Safety Branch.
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