Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys

Abstract

l-DOPA-induced dyskinesias (LID) remain a serious obstacle in the treatment of Parkinson's disease (PD). The objective of this study was to test a new target for treatment of dyskinesias, ethanolamine plasmalogens (PlsEtn). PlsEtn play critical roles in membrane structure mediated functions and as a storage depot of polyunsaturated fatty acids such as docosahexaenoic acid (DHA, omega-3) known to reduce dyskinesias. The motor effect of a daily treatment for 12 days of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Macaca fascicularis monkeys with DHA (100mg/kg) was compared to the DHA-PlsEtn precursor PPI-1011 (50mg/kg). PPI-1011 and DHA reduced LID while maintaining the antiparkinsonian activity of l-DOPA, however the PPI-1011 effect was observed at the first behavioral time point analyzed following drug administration (day 2) whereas the effect of DHA was not observed until after 10 days of administration. DHA treatment increased plasma DHA levels 2–3× whereas PPI-1011 had no effect. DHA and PPI-1011 increased DHA-PlsEtn levels by 1.5–2× while DHA-phosphatidylethanolamine (PtdEtn) levels remained unaffected. DHA treatment also elevated very long chain fatty acid containing PtdEtn and reduced non-DHA containing PtdEtn and PlsEtn levels. PPI-1011 had no effect on these systems. LID scores were inversely correlated with serum DHA-PlsEtn/total PlsEtn ratios levels in DHA and PPI-1011 treated monkeys. Hence, the antidyskinetic activity of DHA and PPI-1011 in MPTP monkeys appears to be associated with the increase of serum DHA-PlsEtn concentrations. This is the first study reporting an antidyskinetic response to augmentation of DHA-PlsEtn using a plasmalogen precursor thus providing a novel drug target for dyskinesias.