A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesia in Parkinsonian Monkeys

Abstract

Background: Phosphodiesterase 10A (PDE10A) is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. PDE10A regulates cAMP and cGMP, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of L-Dopa-induced dyskinesia (LID). The elevation of cAMP/cGMP levels by PDE10A inhibition may thus be targeted to reduce LID. Methods: Five 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID were used. MR1916, a selective PDE10A inhibitor, at doses 0.0015-0.05 mg/kg, s.c. or its vehicle (control test) was co-administered with L-Dopa methyl ester acutely (predetermined optimal and suboptimal s.c. doses) and oral L-Dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and LID by blinded examiners. Pharmacokinetics was also examined. Results: MR1916 consistently reduced LID in acute tests of L-Dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of L-Dopa at the optimal dose. The anti-LID effect of MR1916 (0.015 mg/kg, s.c.) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. Conclusions: Results show that regulation of striatal cyclic nucleotides by PDE10A inhibition could be a useful therapeutic approach for LID, and therefore, data support further studies of selective PDE10A inhibitors for PD therapy.