Phosphodiesterase inhibitors for Parkinson’s Disease therapy

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SUMMARY Parkinson's Disease (PD) is primarily characterized by motor impairment and nigrostriatal dopamine (DA) cell loss. DA replacement with L-Dopa improve mobility initially, but long-term therapy is associated with motor complications including L-Dopa-induced dyskinesias (LIDs). The major effect of DA replacement is the modulation of activity of striatal projection neurons (SPNs). However, non-physiologic, chronic dopaminergic stimulation is associated with maladaptive plasticity and altered SPN responses to DA inputs. DA signaling is mediated by DA receptor activation and its effects on the synthesis of cAMP and cGMP. These nucleotides are also regulated by their catabolic enzymes, the phosphodiesterases (PDEs). Therefore, PDEs may impact the DA signals in SPNs after chronic L-Dopa treatment. This proposal will test the hypothesis that selective phosphodiesterase inhibitors (PDE-Is) may improve motor responses to L-Dopa following chronic treatment. Our hypothesis is based on differential distribution of PDE families in the brain and their specific substrate affinity. These properties suggest that selective PDE-Is target particular cAMP and cGMP mechanisms in SPNs subpopulations and induce specific motor effects. In this project, we plan to analyze the motor effects and physiological striatal correlates of PDE-Is in animal models of PD. Our research plan consists of two specific aims, each with two subaims, to determine behavioral and SPN responses to selective PDE-Is combining primate and rodent models of PD. We will analyze motor and SPN responses to L-Dopa under the effects of PDE-Is (PDE10A, PDE7B, and PDE9 inhibitors). These PDEs are highly expressed in the striatum and have different substrate affinities (cAMP, cGMP, or both). We will use the primate MPTP model of advanced PD for translatability of results. Hemiparkinsonian rats will also be used to refine our cell resolution in the analysis of SPN responses. We will assess parkinsonian motor impairment and LID with established methodologies, appropriate statistical power and rigorous experimental designs. We include electrophysiology (single cell recordings), intracerebral injection of drugs, and calcium indicators (fiber photometry) for analysis of SPN activity in vivo. We will also use transgenic models for assessment of responses to PDE-Is specifically in direct and indirect SPNs. Results of these experiments will shed light on DA signaling in SPN subpopulations, its regulation by PDEs, and associated motor effects of L-Dopa. Our long-term goal is to translate our findings into a new therapeutic approach to reduce aberrant DA signals in SPNs, and improve motor responses to L-Dopa therapy in PD. To this end, we expect to generate significant data with the proposed novel studies of PDE function in PD models.