Can Cyclic Nucleotide Phosphodiesterase Inhibitors Be Drugs for Parkinson's Disease?

Abstract

Parkinson's disease (PD) has no known cure; available therapies are only capable of offering temporary, symptomatic relief to the patients. Varied therapeutic strategies that are clinically used for PD are pharmacological therapies including dopamine replacement therapies (with or without adjuvant), postsynaptic dopamine receptor stimulation, dopamine catabolism inhibitors and also anticholinergics. Surgical therapies like deep brain stimulation and ablative surgical techniques are also employed. Phosphodiesterases (PDEs) are enzymes that degrade the phosphodiester bond in the second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). A number of PDE families are highly expressed in the striatum including PDE1-4, PDE7, PDE9 and PDE10. There are growing evidences to suggest that these enzymes play a critical role in modulating cAMP-mediated dopamine signalling at the postsynaptic region. Therefore, it is clear that PDEs, given the broad range of subtypes and their varied tissue- and region-specific distributions, will be able to provide a range of possibilities as drug targets. There is no phosphodiesterase inhibitor currently approved for use against PD. The development of small molecule inhibitors against cyclic nucleotide PDE is a particularly hot area of investigation, and a lot of research and development is geared in this direction with major players in the pharmaceutical industry investing heavily in developing such potential drug entities. This review, while critically assessing the existing body of literature on brain PDEs with particular interest in the striatum in the context of motor function regulation, indicates it is certainly likely that PDE inhibitors could be developed as therapeutic agents against PD.