Neurodegenerative effects: new mechanism of amphetamines in murine model


Researchers at University of Toronto 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 Peter Wells, lead author of the study that appears in 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 myocardial infarction ) are well understood, but not their long-term consequences."

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 Acetylsalicilic acid ( 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 Acetylsalicilic acid 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 ( prostaglandin H synthase ) 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."

Source: University of Toronto, 2006


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