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.