The Effect of Phosphodiesterase 7 Inhibition on Parkinsonian Motor Behavior in MPTP-treated Non-human Primates Restricted; Files Only

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), leading to motor symptoms such as bradykinesia, akinesia, rigidity, and tremors. Current treatment options for PD are limited, and many patients experience motor complications such as Levodopa-induced dyskinesia (LID) and motor fluctuations with long-term use of Levodopa (L-DOPA), the most effective therapy for managing motor symptoms. Several studies have demonstrated that the activity of striatal projection neurons (SPNs) becomes aberrant in animal models of PD as well as in humans. Phosphodiesterase (PDE) enzymes play a key role in regulating intracellular levels of cyclic nucleotides, including cAMP and cGMP, which are important second messengers involved in DA signaling. Therefore, PDEs may impact the DA signals in SPNs after chronic L-DOPA treatment. PDE inhibitors (PDE-Is) have been proposed as potential therapeutic targets for PD, but their effects on parkinsonian motor behavior and LID are not well understood.

In this study, we investigated the effects of PDE7 inhibition on parkinsonian motor behavior and LID in non-human primates (NHPs) treated with the neurotoxin MPTP. Previous research has shown that systemic administration of a PDE10A inhibitor reduced LID without affecting the antiparkinsonian action of L-DOPA in parkinsonian NHPs. Building on this work, we hypothesized that selective inhibition of PDE7 would improve motor responses to L-DOPA by regulating DA signaling in SPNs. We administered a selective PDE7 inhibitor (PDE7-I) at various doses along with L-DOPA to parkinsonian NHPs. We evaluated motor disability and LID using standardized primate motor scales and assessed potential side effects using the Drug Effects on the Nervous System (DENS) scale. We observed a trend for the PDE7-I to reduce LID when co-administered with the suboptimal and optimal doses of L-DOPA compared to the vehicle. However, the lack of statistical significance may be due to the small sample size and lack of power to detect differences. Future studies with larger sample sizes may be able to replicate and extend these findings.

Table of Contents

Table of Content

Introduction....................................................................................................................................1

           Parkinson’s Disease and Current Treatments......................................................................1

           Dopaminergic Signaling......................................................................................................2

           Phosphodiesterase Inhibitors...............................................................................................4

Research Objectives and Hypothesis...........................................................................................5

Methodology...................................................................................................................................6

           Subjects................................................................................................................................7

           Drugs....................................................................................................................................7

           Behavioral Assessment .......................................................................................................8

           Data Analysis ......................................................................................................................8

Results.............................................................................................................................................8

Discussion.....................................................................................................................................12

Citations........................................................................................................................................17

Figures...........................................................................................................................................25

Appendix.......................................................................................................................................35

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	Parkinson's Disease
Committee Chair / Thesis Advisor	Stella Papa, Emory University
Committee Members	Leah Roesch, Emory University Kristen Frenzel , Emory University

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