Deuterium-L-DOPA - a novel strategy to improve treatment of Parkinson´s disease

Abstract

The dopamine precursor L-DOPA is the standard treatment of Parkinson´s disease (PD). The treatment is associated with a high degree of motoric side effects, L-DOPA induced dyskinesisas (LID). Risk factors for the development of LID are duration of L-DOPA treatment and dosage. Dyskinesia is thought to arise from pulsatile stimulation of dopamine receptors due to the short half-life of L-DOPA. Thus, several strategies are being employed to reduce fluctuating levels of L-DOPA. By means of microdialysis, we have previously shown that the metabolism of dopamine formed from L-DOPA with deuterium-substitutions in the molecule is retarded. In the present study, development of dyskinesias and effect on motor performance were evaluated in the 6-OH-DA-lesion model of PD following treatment with deuteriated-L-DOPA. Unilateral dopaminergic lesions were induced by local injections of 6-OH-DA in rats. Through acute experiments, monitoring rotational behaviour, dose-response curves were established for deuteriated-L-DOPA and L-DOPA. The equipotent dose of deuteriated-L-DOPA was estimated to 63% of L-DOPA. Subsequently, severity of dyskinesia and effect on motor performance in the cylinder-test were evaluated during chronic treatment for three weeks. The equivalent dose of deuteriated-L-DOPA resulted in an enhanced effect on motor performance and the same degree of dyskinesia as compared to L-DOPA. The equipotent dose of deuteriated-L-DOPA resulted in less dyskinesia compared to L-DOPA with equal improvement of motor performance in the cylinder-test. In conclusion, the reduced metabolism of dopamine formed from deuteriated-L-DOPA allows a significant dose-reduction without loss of anti-parkinsonian effect and a lower degree of dyskinesias. Deuteriated-L-DOPA may significantly improve PD-treatment.