(06-05-06) DHA Eases Side Effects of Parkinson?s Disease Medication in Animal Model

Sometimes, living to a ?ripe old age? brings with it impaired brain function. One disorder that may develop after the age of 65 is Parkinson?s disease, a brain condition characterized by tremors or shaking, slow movements, stiffness, and poor balance. The disease results from deterioration of the substantia nigra (Figure 1), a part of the basal ganglia deep inside the brain. Cells in this region produce chemical transmitters, substances that relay messages between cells. The chief neurotransmitter of the substantia nigra is dopamine, a chemical involved in the planning and controlling the body?s automatic movements. When dopamine becomes depleted, acetylcholine, another neurotransmitter steps in to take its place, thereby creating an imbalance.

Parkinson?s disease is often treated with levodopa (L-dopa), a substance the brain converts to dopamine. Unfortunately, treatment with L-dopa may be accompanied by dyskinesia?involuntary distorted movements. Once established, dyskinesia is virtually impossible to eliminate. It has been suggested that L-dopa creates long-lasting changes in the neural responses to dopamine. In the paper described here, the long-chain omega-3 polyunsaturated fatty acid (n-3 LC-PUFA) docosahexaenoic acid (DHA) reduced or delayed the dyskinesia associated with L-dopa treatment in an animal model of Parkinson?s disease.

Much experimental research on Parkinson?s disease is conducted in monkeys treated with MPTP, a chemical that mimics the human condition. Studies with this model suggest that L-dopa-induced dyskinesia results from nonphysiological stimulation of the dopamine receptors. DHA enters the picture because it is the major PUFA in neuronal cell membranes and was reported to affect dopamine concentrations in brain, increase the number of dopamine-producing cells in cultured neuronal cells, and reduce the dyskinesia associated with antipsychotic drug treatment in mice. Interestingly, dyskinesia is sometimes associated with chronic use of antipsychotic medications. These connections suggested that DHA might reduce the dyskinesia associated with L-dopa treatment in Parkinson?s disease. To evaluate this possibility, Dr. Samadi and colleagues at Laval University, Quebec, Canada, studied the effects of DHA in the monkey model of Parkinson?s disease.

In these experiments, the investigators used two models of dyskinesia. The first model was designed to determine whether DHA affected dyskinesia once it had developed. MPTP-treated monkeys exhibiting Parkinson?s syndrome were treated with a daily dose of L-dopa and its related enzyme inhibitor, benserazide, given to prevent breakdown of the L-dopa in the blood, until dyskinesia developed. Once the dyskinesia was established, subsequent doses of L-dopa reproduced the abnormal movements. DHA at 100 mg/kg body weight (average 300 to 350 mg/animal) was administered subcutaneously for 8 days in the first study with this model, and orally (by stomach tube) at twice the dose for 12 days in the experiment, after a washout period of several months. Treatment changed from subcutaneous to oral delivery because of irritation at the injection site and the dose was doubled to allow for possible digestive losses.

The third experiment tested whether DHA could prevent or delay the development of L-dopa-induced dyskinesia in parkinsonian animals. The investigators used a different model of dyskinesia, giving MPTP-treated animals 100 mg DHA/kg body weight or the delivery vehicle without DHA for 3 days prior to treatment with L-dopa. Subsequently, DHA was given daily with the oral L-dopa for 1 month.

Dyskinesia was scored for each animal at baseline and after every 2 days in the first two studies, and after each week in the third study. Dyskinesia scores were based on behavioral ratings of abnormal movements of the face, neck, trunk, arms, and legs, plus assessments of amplitude, interference with normal motor activity, and frequency of abnormal movements. Severity of parkinsonianism was rated according to published scales with maximal disability scored at 16.

Results from the first experiment indicated that provision of DHA with L-dopa to parkinsonian monkeys exhibiting dyskinesia reduced the dyskinesia scores significantly by 35% by the fourth day of treatment (P<0.05) compared with animals receiving only L-dopa. Scores remained improved for the duration of treatment, but returned to pretreatment values 5 days after DHA was discontinued. DHA treatment alone had no effect on antiparkinsonian activity associated with L-dopa, or on parkinsonian and dyskinetic scores. Results were similar for DHA administration subcutaneously and orally, although findings were somewhat delayed with the oral dose.

In the third experiment, where DHA was given for 3 days prior to the development of L-dopa-induced dyskinesia and then subsequently with the L-dopa, onset of dyskinesia was delayed, but increased gradually with time. Compared with animals receiving only L-dopa and the DHA-delivery vehicle (8% polyethylene glycol-600 in water), animals pretreated with DHA and given DHA with L-dopa, development of dyskinesia was delayed and less severe. The mean and maximum dyskinesia scores induced by L-dopa over the 1-month treatment were reduced by 40% and 46%, respectively in the DHA-treated animals compared with animals not receiving DHA. Over the 1-month study, onset of symptoms was delayed and severity reduced. Cumulative scores for dyskinesia over the 1-month study were reduced by 60% the DHA-treated group compared with the unsupplemented animals. As in the first experiment, DHA had no effect on the parkinsonian symptoms themselves.

The authors noted considerable variability in individual responses to DHA supplementation. Two of the four animals had almost no dyskinesia, one had intermediate responses, and the other was similar to the unsupplemented animals. What is not known from these observations is whether the differences observed with DHA treatment over one month would be sustained. The time curves shown in the original paper suggest that both groups had reached their maximum scores by this time, even though the difference between the groups did not achieve statistical significance at 4 weeks. A larger sample might have permitted firmer conclusions.

These findings could imply important clinical benefits for people suffering from the medication-induced side effects of L-dopa. First, DHA yielded significant and substantial (40%) reductions in L-dopa-induced dyskinesia that lasted throughout the course of L-dopa treatment. Second, DHA did not interfere with the treatment benefits of L-dopa, unlike many of the pharmaceutical options available. DHA appeared to be well tolerated and without adverse effects. The effects of
DHA on dyskinesia were achieved with relatively high doses of DHA, equivalent to an intake of 5 to 10 gm/day. Whether more modest amounts would be effective is not known, but worth finding out. DHA deserves evaluation in patients with Parkinson?s disease whose quality of life could be meaningfully enhanced.

Source: Samadi P, Gregoire L, Rouillard C, Bedard PJ, Di Paolo T, Levesque D. Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine monkeys. Ann Neurol 2005;60:1-6.

News

---

In evidenza

"L'informazione presente nel sito serve a migliorare, e non a sostituire, il rapporto medico-paziente."

Per coloro che hanno problemi di salute si consiglia di consultare sempre il proprio medico curante.