News-Medical.net

 Durham, N.C. --


Amphetamines, including the drug popularly known as Ecstasy, can reverse the
symptoms of Parkinson's disease in mice with an acute form of the condition,
according to new research at Duke University Medical Center.


The researchers caution that the findings in animals do not suggest
Parkinson's disease patients should find relief by taking amphetamines, which
are drugs of abuse with many dangerous side effects. The findings rather
indicate that drugs with similar chemical attributes might offer useful
alternatives to current therapies, the researchers said.


The new study also shows that amphetamines -- normally thought to act by
increasing dopamine concentrations in the brain -- correct the behavioral
abnormalities associated with Parkinson's in mice devoid of the brain
messenger. Dopamine normally acts on dopamine receptors -- protein switches
on the surface of neurons -- to stimulate brain processes that affect
movement, emotion, pleasure and mood.


Parkinson's disease stems from the degeneration of neurons in a brain region
that controls movement. That degeneration, in turn, leads to a shortage of
the chemical messenger dopamine. The finding that amphetamines can alter
movement independently of dopamine opens up new directions in the search for
prospective anti-Parkinsonian drugs, the researchers said.


The researchers, led by James B. Duke professor of cell biology Marc Caron,
Ph.D. and Assistant Research Professor Raul Gainetdinov, M.D., Ph.D., of
Duke, made the discovery after testing the utility of more than 60 compounds
for reversing Parkinson's symptoms in a mouse model of the disease. Developed
by the Duke team, the mice lack detectable brain levels of dopamine and
experience essentially all the symptoms of Parkinson's disease for several
hours before recovering their normal behavior. Caron is also a researcher of
the Duke Institute for Genome Sciences & Policy.


The team reports its findings in the August 2005 issue of Public Library of
Science (PLoS) Biology. The research was sponsored by the National Institutes
of Health and a donation from The Long Island Community Foundation, a
division of The New York Community Trust.


"This model is exciting because it allows us to examine the potential
contribution of systems other than dopamine to Parkinson's disease," said
Caron. "We may be able to discover avenues for treatment that had never been
thought about before or that were impossible to investigate."


The new mouse model enables the researchers to acutely eliminate dopamine,
exposing systems contributing to the disease that may not have been obvious
before, he explained. The severity of disease symptoms in the mice also
provides a very sensitive test for compounds with potential therapeutic
value, the researchers said.


In the United States, at least 500,000 people suffer from Parkinson's disease,
and about 50,000 new cases are reported annually, according to the National
Institute of Neurological Disorders and Stroke. These figures are expected to
rise as the average age of the population increases. Symptoms of the disease
include tremors, slow movement or an inability to move, rigid limbs and a
shuffling gait. Progression of the disease also leads to severe impairment in
cognitive function.


Dopamine replacement therapy which involves administration of the dopamine
precursor, L-DOPA, remains the gold standard for Parkinson's treatment, said
Tatyana Sotnikova, Ph.D., of Duke. However, the efficacy of the therapy wanes
with time, and patients often develop fluctuations in motor performance and
other adverse reactions.


In the current study, the researchers treated mice unable to recycle dopamine
with a drug that also prevented them from manufacturing the brain messenger.
The brains of the mice therefore lack detectable levels of dopamine and the
animals exhibit all the symptoms of Parkinson's disease for up to 16 hours.
Those symptoms included severely impaired movement, rigidity and tremor. When
treated with L-DOPA, the symptoms disappeared as the animals resumed normal
movement.


Surprisingly, the researchers reported, treating mice lacking dopamine with
high doses of amphetamine derivatives including methamphetamine and MDMA,
otherwise known as Ecstasy reversed those symptoms. Ecstasy was most
effective at counteracting the manifestations of Parkinson's symptoms in the
mice, with the beneficial effects becoming more pronounced with increasing
dose.


The researchers also report that low doses of amphetamines could, when
combined with L-DOPA, potentiate minimally effective doses of L-DOPA in the
mice. This could have important considerations in reducing some of the side
effects of current therapy.


"The locomotor stimulating effect of amphetamine and its derivatives are
classically thought to result from a massive flood of dopamine," said
Sotnikova. "However, the mice have only a tiny fraction of dopamine, which
cannot be recycled, precluding a rise in dopamine as the possible mechanism.


"Taken together, the findings indicate that Ecstasy can improve movement
control independently of dopamine and, most importantly provide evidence that
drug activation of other neuronal pathways may be sufficient to restore
movement even in the virtual absence of dopamine neurotransmission," she
added.


Amphetamines might reverse the animal's symptoms through their effects on a
different group of receptors called trace amine receptors, the researchers
suggested. Recent evidence showed that amphetamines act on trace amine
receptors in addition to dopamine transmission, yet little is known about
their physiological role in mammals.


The current findings are particularly promising given the severity of symptoms
in the mice completely lacking dopamine, said Gainetdinov. "We think that
this new animal model provides a much more stringent test for potential drugs
that might prove efficacious in patients with Parkinson's disease."


Many of the previously developed animal models of Parkinson's disease have
reduced, but detectable, levels of dopamine and do not show all the
characteristics of Parkinson's disease, making studies of potential
therapeutic methods in those animals less clear, Gainetdinov said. On the
other hand, animals permanently lacking dopamine cannot survive, he added.


While the results are promising, the researchers cautioned, Ecstasy's ability
to stimulate movement in the mice occurred only with high doses of the drug.
Such high doses might destroy nerve tissue in normal mice and in humans, who
are generally more sensitive than mice to such drugs.


"Amphetamines are controversial drugs, and there's no reason to suggest that
amphetamines themselves should be used to treat Parkinson's," Gainetdinov
said. "However, the chemical structure of amphetamines may lead to new,
amphetamine-like drugs, that might provide a more lasting and beneficial
alternative to L-DOPA in the treatment of Parkinson's disease."


Collaborators on the study include Jean-Martin Beaulieu, Larry S. Barak and
William C. Wetsel all of Duke.

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn