Sci. Aging Knowl. Environ., 14 May 2003
Everything in Moderation
New approach might soothe a side effect of Parkinson's disease treatment
Key Words: dyskinesia dystonic globus pallidus partial agonist
Like many famous savants, Goldilocks favored moderation. But moderation might lead to more than a comfortable bed--it could also be the key to controlling the erratic movements caused by a standard Parkinson's disease (PD) treatment. A compound that mildly stimulates a brain receptor quells the side effect in monkeys, according to a new study. The work suggests a way to reduce the unpleasantness of therapy without diminishing the benefits.
PD patients lose large numbers of neurons that make the neurotransmitter dopamine, which triggers symptoms such as rigid muscles, impaired coordination, and tremors. For more than 30 years, L-dopa, a compound that the brain transforms into dopamine, has been the mainstay of PD treatment. However, after taking the drug for several years, many patients begin to suffer violent, unconscious movements (see Parkinson's Disease Case Study). Doctors have tried without success to prevent these jerks and spasms by adjusting L-dopa doses and by chasing it with other drugs. Researchers don't know the cause of these disabling movements, but accumulating evidence implicates the D3 receptor, one of several brain proteins that respond to dopamine. For example, rats with PD-like damage spin when given L-dopa, and blocking the D3 receptor curtails this behavior, according to work by molecular pharmacologist Pierre Sokoloff of INSERM in Paris, France, and colleagues. Although the ticks and jerks of PD patients differ from rodent rotations, Sokoloff and colleagues suspected that D3 might underlie human symptoms.
As a first step toward testing this idea, the researchers dosed monkeys with MPTP, a compound that spurs PD-like symptoms. The scientists then measured the number of D3 receptors in brain slices from monkeys treated with L-dopa that showed abnormal movements, treated monkeys that didn't have the side effect, and untreated controls. Animals with the abnormal movements carried the largest number of D3 receptors in two brain regions that govern movement, and the receptor count correlated with the intensity of symptoms. The findings suggest that L-dopa hikes the number of D3 receptors and that this boost sparks the erratic movements, says Sokoloff. The researchers then dosed some monkeys with L-dopa and a compound that stimulates the D3 receptor about half as strongly as dopamine does. The combo treatment cut the severity of abnormal movements by 66% and prevented recurrence of PD symptoms. The compound works by tying up receptors to which L-dopa would normally bind, says Sokoloff. Mixing L-dopa with drugs that temper the firing of the D3 receptor could damp the side effect in patients, he adds.
"It's a very important paper," says Jeffrey Joyce, a neuroscientist at the Sun Health Research Institute in Sun City, Arizona. "They've identified a mechanism by which one could directly modify that [side effect] while retaining the therapeutic effectiveness." Neurologist Jon Stoessl of the University of British Columbia in Vancouver, Canada, agrees and adds that the same strategy of partial stimulation might help squelch the wild movements caused by some antipsychotic medications. Parkinson's patients might regain control over their limbs with future drugs that make the amount of D3 firing just right.
--Mitch Leslie; suggested by Amir Sadighi Akha
May 14, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150