Phosphodiesterase 7 inhibition reduces L-DOPA-induced dyskinesias in parkinsonian nonhuman primates

Abstract

The mechanisms underlying L-DOPA-induced dyskinesia (LID) largely arise from maladaptive plasticity in striatal circuits leading to altered neuronal responses to dopamine (DA) signaling. Cyclic nucleotides play a major role in the molecular cascades of DA signaling, and particularly cAMP is known to be associated with LID mechanisms. Cyclic nucleotide levels in striatal neurons are regulated by phosphodiesterases (PDEs), and 1 isoenzyme with selective affinity for cAMP and high expression in the striatum is PDE7. Here, the PDE7 inhibitor OMS-401 was evaluated for antidyskinetic effects in a nonhuman primate (NHP) model of advanced Parkinson's disease. A series of systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration followed by chronic L-DOPA treatment were used to induce advanced parkinsonism and reproducible LID in a group of 3 macaques. The effects of the PDE7 inhibitor OMS-401 were analyzed with a dose-response curve design in coadministration trials for 2 doses of L-DOPA (optimal and suboptimal). Motor disability, LID, and drug adverse reactions were assessed using standardized scales for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated NHPs. OMS-401 significantly reduced LIDs in a dose-dependent fashion without interacting with the antiparkinsonian action of L-DOPA or inducing side effects in parkinsonian NHPs. Results confirm that cAMP levels in striatal neurons play a critical role in LID mechanisms, and that PDE7 inhibition may be a strategy to control LID over the long-term DA replacement therapy in Parkinson's disease. SIGNIFICANCE STATEMENT: This study shows that selective phosphodiesterase 7 inhibition with OMS-401 reduces dyskinesia in a Parkinson's primate model without affecting L-DOPA's benefits. Phosphodiesterase 7 inhibition may offer a promising approach for L-DOPA-induced dyskinesia management, providing an alternative to treatments with dose-limiting side effects.

Keywords: Cyclic adenosine monophosphate; L-DOPA-induced dyskinesia; Nonhuman primates; Parkinson’s disease; Phosphodiesterase 7; Striatum.