Phosphodiesterases: Regulators of cyclic nucleotide signals and novel molecular target for movement disorders Sorabh Sharma, Kushal Kumar, Rahul Deshmukh n , Pyare Lal Sharma Q1 Neuropharmacology Division, I. S. F. College of Pharmacy, Moga-142001, Punjab, India article info Article history: Received 25 December 2012 Received in revised form 16 June 2013 Accepted 21 June 2013 Keywords: Cyclic nucleotides Dyskinesia's Huntington's disease Movement disorders Parkinson's disease Phosphodiesterase inhibitors abstract Movement disorders rank among the most common neurological disorders. During the last two decades substantial progress has been made in understanding of the pathological basis of these disorders. Although, several mechanisms have been proposed, downregulation of cyclic nucleotide mediated signaling cascade has consistently been shown to contribute to the striatal dysfunctioning as seen in movement disorders. Thus, counteracting dysregulated cyclic nucleotide signaling has been considered to be beneficial in movement disorders. Cyclic nucleotide phosphodiesterases (PDEs) are the enzymes responsible for the breakdown of cyclic nucleotides and upregulation in PDE activity has been reported in various movement disorders. Thus, PDE inhibition is considered to be a novel strategy to restore cerebral cyclic nucleotide levels and their downstream signalling cascade. Indeed, various PDE inhibitors have been tested pre-clinically and were reported to be neuroprotective in various neurodegenerative disorders associated with movement disabilities. In this review, we have discussed a putative role of PDE inhibitors in movement disorders and associated abnormalities. & 2013 Elsevier B.V. All rights reserved. Contents 1. Introduction .......................................................................................................... 1 2. Phosphodiesterases .................................................................................................... 3 2.1. Structure of phosphodiesterases .................................................................................... 3 2.2. Cyclic nucleotide signaling ........................................................................................ 3 2.3. Phosphodiesterases in movement disorders........................................................................... 4 3. Phosphodiesterases in hypokinetic movement disorders ...................................................................... 4 3.1. Phosphodiesterases in Parkinson's disease ............................................................................ 4 3.1.1. Phosphodiesterase 1 ...................................................................................... 5 3.1.2. Phosphodiesterase 4 ...................................................................................... 5 3.1.3. Phosphodiesterase 7 ...................................................................................... 6 3.1.4. Phosphodiesterase 10 ..................................................................................... 6 3.1.5. Levodopa-induced dyskinesia's (LIDs) ......................................................................... 6 4. Phosphodiesterases in hyperkinetic movement disorders ...................................................................... 6 4.1. Phosphodiesterases in Huntington's disease .......................................................................... 6 4.1.1. Phoshodiesterase 1 ....................................................................................... 7 4.1.2. Phosphodiesterase 4 ...................................................................................... 7 4.1.3. Phosphodiesterase 5 ...................................................................................... 7 4.1.4. Phosphodiesterase 10 ..................................................................................... 7 5. Other movement disorders .............................................................................................. 8 5.1. Tardive dyskinesia ............................................................................................... 8 6. Conclusion ........................................................................................................... 8 Uncited references ........................................................................................................ 8 Acknowledgements ........................................................................................................ 8 References ............................................................................................................... 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology 0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.06.038 n Corresponding author. Tel.: +91 99889 04375; fax: +91 1636 239515. E-mail address: login2rd@gmail.com (R. Deshmukh). Please cite this article as: Sharma, S., et al., Phosphodiesterases: Regulators of cyclic nucleotide signals and novel molecular target for movement disorders. Eur J Pharmacol (2013), http://dx.doi.org/10.1016/j.ejphar.2013.06.038i European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎