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Molecular Neurobiology

, Volume 55, Issue 1, pp 822–834 | Cite as

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

  • Dominic Ngima Nthenge-Ngumbau
  • Kochupurackal P. MohanakumarEmail author
Article

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.

Keywords

cAMP signalling Pharmacological PDE inhibitors Postsynaptic regulation of motor function Striatum Dopamine 

Notes

Acknowledgements

DNN-N acknowledges the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India; the Centre for International Corporation in Science (CICS); and The World Academy of Science (TWAS) for international DBT-TWAS postgraduate fellowship. KPM received grant from the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, for a project entitled: “PDE-IV as target for Parkinson’s disease: synthesis of congeners of irsogladine, and their evaluation in cellular and animal models of the disease” (Project ID No. GAP-0292, Sanction order no. BT/PR3895/MED/97/6/2011).

References

  1. 1.
    Pringsheim T, Jette N, Frolkis A, Steeves TD (2014) The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 29(13):1583–1590. doi: 10.1002/mds.25945 PubMedCrossRefGoogle Scholar
  2. 2.
    Mohanakumar KP, Chandra G, Haobam R, Selley ML (2009) Treatment of brain disorders. US20090143388 A1,Google Scholar
  3. 3.
    Bergmann JE, Cutshall NS, Demopulos GA, Florio VA, Gaitanaris GA, Gray P, Hohmann J, Onrust R, Zeng H (2011) Use of PDE7 inhibitors for the treatment of movement disorders. Google PatentsGoogle Scholar
  4. 4.
    Gil AM, Ayuso-Gontan CG, Martín CP, Castillo AP, García JM, Redondo M, Cristóbal MSS (2012) Use of quinazoline derivatives for neurodegenerative diseases. Google Patents,Google Scholar
  5. 5.
    Kelly PJ, Ahlskog JE, Goerss SJ, Daube JR, Duffy JR, Kall BA (1987) Computer-assisted stereotactic ventralis lateralis thalamotomy with microelectrode recording control in patients with Parkinson’s disease. Mayo Clin Proc 62(8):655–664PubMedCrossRefGoogle Scholar
  6. 6.
    Narabayashi H, Yokochi F, Nakajima Y (1984) Levodopa-induced dyskinesia and thalamotomy. J Neurol Neurosurg Psychiatry 47(8):831–839PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Vitek JL, Bakay RA, Freeman A, Evatt M, Green J, McDonald W, Haber M, Barnhart H et al (2003) Randomized trial of pallidotomy versus medical therapy for Parkinson’s disease. Ann Neurol 53(5):558–569. doi: 10.1002/ana.10517 PubMedCrossRefGoogle Scholar
  8. 8.
    Parkin S, Nandi D, Giladi N, Joint C, Gregory R, Bain P, Scott R, Aziz TZ (2001) Lesioning the subthalamic nucleus in the treatment of Parkinson’s disease. Stereotact Funct Neurosurg 77(1–4):68–72PubMedCrossRefGoogle Scholar
  9. 9.
    Walter BL, Vitek JL (2004) Surgical treatment for Parkinson’s disease. Lancet Neurol 3(12):719–728. doi: 10.1016/S1474-4422(04)00934-2 PubMedCrossRefGoogle Scholar
  10. 10.
    Hickey P, Stacy M (2016) Deep brain stimulation: a paradigm shifting approach to treat Parkinson’s disease. Front Neurosci 10:173. doi: 10.3389/fnins.2016.00173 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    McIntyre CC, Anderson RW (2016) Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation. J Neurochem. doi: 10.1111/jnc.13649 PubMedPubMedCentralGoogle Scholar
  12. 12.
    Groppa S, Herzog J, Falk D, Riedel C, Deuschl G, Volkmann J (2014) Physiological and anatomical decomposition of subthalamic neurostimulation effects in essential tremor. Brain 137(Pt 1):109–121. doi: 10.1093/brain/awt304 PubMedCrossRefGoogle Scholar
  13. 13.
    Kuhn AA, Tsui A, Aziz T, Ray N, Brucke C, Kupsch A, Schneider GH, Brown P (2009) Pathological synchronisation in the subthalamic nucleus of patients with Parkinson’s disease relates to both bradykinesia and rigidity. Exp Neurol 215(2):380–387. doi: 10.1016/j.expneurol.2008.11.008 PubMedCrossRefGoogle Scholar
  14. 14.
    DeLong MR, Wichmann T (2015) Basal ganglia circuits as targets for neuromodulation in Parkinson disease. JAMA Neurol 72(11):1354–1360. doi: 10.1001/jamaneurol.2015.2397 PubMedCrossRefGoogle Scholar
  15. 15.
    van Kuyck K, Welkenhuysen M, Arckens L, Sciot R, Nuttin B (2007) Histological alterations induced by electrode implantation and electrical stimulation in the human brain: a review. Neuromodulation 10(3):244–261. doi: 10.1111/j.1525-1403.2007.00114.x PubMedCrossRefGoogle Scholar
  16. 16.
    Neve KA, Seamans JK, Trantham-Davidson H (2004) Dopamine receptor signaling. J Recept Signal Transduct Res 24(3):165–205PubMedCrossRefGoogle Scholar
  17. 17.
    Kebabian JW, Greengard P (1971) Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission. Science 174(4016):1346–1349PubMedCrossRefGoogle Scholar
  18. 18.
    Lakics V, Karran EH, Boess FG (2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59(6):367–374. doi: 10.1016/j.neuropharm.2010.05.004 PubMedCrossRefGoogle Scholar
  19. 19.
    Repaske DR, Corbin JG, Conti M, Goy MF (1993) A cyclic GMP-stimulated cyclic nucleotide phosphodiesterase gene is highly expressed in the limbic system of the rat brain. Neuroscience 56(3):673–686PubMedCrossRefGoogle Scholar
  20. 20.
    Snyder PB, Esselstyn JM, Loughney K, Wolda SL, Florio VA (2005) The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis. J Lipid Res 46(3):494–503. doi: 10.1194/jlr.M400362-JLR200 PubMedCrossRefGoogle Scholar
  21. 21.
    Ramirez AD, Smith SM (2014) Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. Cent Nerv Syst Agents Med Chem 14(2):72–82PubMedCrossRefGoogle Scholar
  22. 22.
    Polli JW, Kincaid RL (1994) Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation. J Neurosci 14(3 Pt 1):1251–1261PubMedGoogle Scholar
  23. 23.
    Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58(3):488–520. doi: 10.1124/pr.58.3.5 PubMedCrossRefGoogle Scholar
  24. 24.
    Stephenson DT, Coskran TM, Wilhelms MB, Adamowicz WO, O’Donnell MM, Muravnick KB, Menniti FS, Kleiman RJ et al (2009) Immunohistochemical localization of phosphodiesterase 2A in multiple mammalian species. J Histochem Cytochem 57(10):933–949. doi: 10.1369/jhc.2009.953471 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Stephenson DT, Coskran TM, Kelly MP, Kleiman RJ, Morton D, O’Neill SM, Schmidt CJ, Weinberg RJ et al (2012) The distribution of phosphodiesterase 2A in the rat brain. Neuroscience 226:145–155. doi: 10.1016/j.neuroscience.2012.09.011 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Reyes-Irisarri E, Markerink-Van Ittersum M, Mengod G, de Vente J (2007) Expression of the cGMP-specific phosphodiesterases 2 and 9 in normal and Alzheimer’s disease human brains. Eur J Neurosci 25(11):3332–3338. doi: 10.1111/j.1460-9568.2007.05589.x PubMedCrossRefGoogle Scholar
  27. 27.
    Masciarelli S, Horner K, Liu C, Park SH, Hinckley M, Hockman S, Nedachi T, Jin C et al (2004) Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. J Clin Invest 114(2):196–205. doi: 10.1172/JCI21804 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Holmstrom K, Rasmussen OF (1990) An easy method to check the efficiency of biotin end-labelling of DNA-fragments. Nucleic Acids Res 18(15):4632PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Perez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G (2000) Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and[3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 20(3–4):349–374PubMedCrossRefGoogle Scholar
  30. 30.
    Johansson EM, Reyes-Irisarri E, Mengod G (2012) Comparison of cAMP-specific phosphodiesterase mRNAs distribution in mouse and rat brain. Neurosci Lett 525(1):1–6. doi: 10.1016/j.neulet.2012.07.050 PubMedCrossRefGoogle Scholar
  31. 31.
    Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370(Pt 1):1–18. doi: 10.1042/BJ20021698 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    DaSilva JN, Lourenco CM, Meyer JH, Hussey D, Potter WZ, Houle S (2002) Imaging cAMP-specific phosphodiesterase-4 in human brain with R-[11C]rolipram and positron emission tomography. Eur J Nucl Med Mol Imaging 29(12):1680–1683. doi: 10.1007/s00259-002-0950-y PubMedCrossRefGoogle Scholar
  33. 33.
    Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13(4):290–314. doi: 10.1038/nrd4228 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Keravis T, Lugnier C (2012) Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 165(5):1288–1305. doi: 10.1111/j.1476-5381.2011.01729.x PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5(8):660–670. doi: 10.1038/nrd2058 PubMedCrossRefGoogle Scholar
  36. 36.
    Perez-Torres S, Cortes R, Tolnay M, Probst A, Palacios JM, Mengod G (2003) Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer’s disease brains examined by in situ hybridization. Exp Neurol 182(2):322–334PubMedCrossRefGoogle Scholar
  37. 37.
    Kobayashi T, Gamanuma M, Sasaki T, Yamashita Y, Yuasa K, Kotera J, Omori K (2003) Molecular comparison of rat cyclic nucleotide phosphodiesterase 8 family: unique expression of PDE8B in rat brain. Gene 319:21–31PubMedCrossRefGoogle Scholar
  38. 38.
    Tsai LC, Chan GC, Nangle SN, Shimizu-Albergine M, Jones GL, Storm DR, Beavo JA, Zweifel LS (2012) Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay. Genes Brain Behav 11(7):837–847. doi: 10.1111/j.1601-183X.2012.00836.x PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    van Staveren WC, Glick J, Markerink-van Ittersum M, Shimizu M, Beavo JA, Steinbusch HW, de Vente J (2002) Cloning and localization of the cGMP-specific phosphodiesterase type 9 in the rat brain. J Neurocytol 31(8–9):729–741PubMedCrossRefGoogle Scholar
  40. 40.
    Andreeva SG, Dikkes P, Epstein PM, Rosenberg PA (2001) Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain. J Neurosci 21(22):9068–9076PubMedGoogle Scholar
  41. 41.
    Soderling SH, Bayuga SJ, Beavo JA (1998) Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 273(25):15553–15558PubMedCrossRefGoogle Scholar
  42. 42.
    Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA (1999) Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase. Gene 234(1):109–117PubMedCrossRefGoogle Scholar
  43. 43.
    Soderling SH, Bayuga SJ, Beavo JA (1999) Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci U S A 96(12):7071–7076PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Seeger TF, Bartlett B, Coskran TM, Culp JS, James LC, Krull DL, Lanfear J, Ryan AM et al (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985(2):113–126PubMedCrossRefGoogle Scholar
  45. 45.
    Coskran TM, Morton D, Menniti FS, Adamowicz WO, Kleiman RJ, Ryan AM, Strick CA, Schmidt CJ et al (2006) Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J Histochem Cytochem 54(11):1205–1213. doi: 10.1369/jhc.6A6930.2006 PubMedCrossRefGoogle Scholar
  46. 46.
    Loughney K, Taylor J, Florio VA (2005) 3′,5′-Cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res 17(4):320–325. doi: 10.1038/sj.ijir.3901317 PubMedCrossRefGoogle Scholar
  47. 47.
    Kelly MP (2015) Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target? Curr Pharm Des 21(3):389–416PubMedCrossRefGoogle Scholar
  48. 48.
    Francis SH (2005) Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res 17(5):467–468. doi: 10.1038/sj.ijir.3901377 PubMedCrossRefGoogle Scholar
  49. 49.
    Morales-Garcia JA, Redondo M, Alonso-Gil S, Gil C, Perez C, Martinez A, Santos A, Perez-Castillo A (2011) Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease. PLoS One 6(2):e17240. doi: 10.1371/journal.pone.0017240 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Reed TM, Repaske DR, Snyder GL, Greengard P, Vorhees CV (2002) Phosphodiesterase 1B knock-out mice exhibit exaggerated locomotor hyperactivity and DARPP-32 phosphorylation in response to dopamine agonists and display impaired spatial learning. J Neurosci 22(12):5188–5197PubMedGoogle Scholar
  51. 51.
    Ehrman LA, Williams MT, Schaefer TL, Gudelsky GA, Reed TM, Fienberg AA, Greengard P, Vorhees CV (2006) Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice. Genes Brain Behav 5(7):540–551. doi: 10.1111/j.1601-183X.2006.00209.x PubMedCrossRefGoogle Scholar
  52. 52.
    Girault JA (2012) Signaling in striatal neurons: the phosphoproteins of reward, addiction, and dyskinesia. Prog Mol Biol Transl Sci 106:33–62. doi: 10.1016/B978-0-12-396456-4.00006-7 PubMedCrossRefGoogle Scholar
  53. 53.
    Sancesario G, Giorgi M, D’Angelo V, Modica A, Martorana A, Morello M, Bengtson CP, Bernardi G (2004) Down-regulation of nitrergic transmission in the rat striatum after chronic nigrostriatal deafferentation. Eur J Neurosci 20(4):989–1000. doi: 10.1111/j.1460-9568.2004.03566.x PubMedCrossRefGoogle Scholar
  54. 54.
    Sharma S, Deshmukh R (2015) Vinpocetine attenuates MPTP-induced motor deficit and biochemical abnormalities in Wistar rats. Neuroscience 286:393–403. doi: 10.1016/j.neuroscience.2014.12.008 PubMedCrossRefGoogle Scholar
  55. 55.
    Laddha SS, Bhatnagar SP (2009) A new therapeutic approach in Parkinson’s disease: some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents. Bioorg Med Chem 17(19):6796–6802. doi: 10.1016/j.bmc.2009.08.041 PubMedCrossRefGoogle Scholar
  56. 56.
    Rosman GJ, Martins TJ, Sonnenburg WK, Beavo JA, Ferguson K, Loughney K (1997) Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase. Gene 191(1):89–95PubMedCrossRefGoogle Scholar
  57. 57.
    Sonnenburg WK, Mullaney PJ, Beavo JA (1991) Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase cDNA. Identification and distribution of isozyme variants. J Biol Chem 266(26):17655–17661PubMedGoogle Scholar
  58. 58.
    Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65(5):585–596. doi: 10.1016/j.neuron.2010.02.014 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Missale C, Fiorentini C, Collo G, Spano P (2010) The neurobiology of dopamine receptors: evolution from the dual concept to heterodimer complexes. J Recept Signal Transduct Res 30(5):347–354. doi: 10.3109/10799893.2010.506192 PubMedCrossRefGoogle Scholar
  60. 60.
    Sierksma AS, Rutten K, Sydlik S, Rostamian S, Steinbusch HW, van den Hove DL, Prickaerts J (2013) Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Neuropharmacology 64:124–136. doi: 10.1016/j.neuropharm.2012.06.048 PubMedCrossRefGoogle Scholar
  61. 61.
    Rodefer JS, Saland SK, Eckrich SJ (2012) Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology 62(3):1182–1190. doi: 10.1016/j.neuropharm.2011.08.008 PubMedCrossRefGoogle Scholar
  62. 62.
    Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J et al (2004) Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47(7):1081–1092. doi: 10.1016/j.neuropharm.2004.07.040 PubMedCrossRefGoogle Scholar
  63. 63.
    Reinhardt RR, Bondy CA (1996) Differential cellular pattern of gene expression for two distinct cGMP-inhibited cyclic nucleotide phosphodiesterases in developing and mature rat brain. Neuroscience 72(2):567–578PubMedCrossRefGoogle Scholar
  64. 64.
    Movsesian M (2016) Novel approaches to targeting PDE3 in cardiovascular disease. Pharmacol Ther 163:74–81. doi: 10.1016/j.pharmthera.2016.03.014 PubMedCrossRefGoogle Scholar
  65. 65.
    Begum N, Hockman S, Manganiello VC (2011) Phosphodiesterase 3A (PDE3A) deletion suppresses proliferation of cultured murine vascular smooth muscle cells (VSMCs) via inhibition of mitogen-activated protein kinase (MAPK) signaling and alterations in critical cell cycle regulatory proteins. J Biol Chem 286(29):26238–26249. doi: 10.1074/jbc.M110.214155 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Choi YH, Park S, Hockman S, Zmuda-Trzebiatowska E, Svennelid F, Haluzik M, Gavrilova O, Ahmad F et al (2006) Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice. J Clin Invest 116(12):3240–3251. doi: 10.1172/JCI24867 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Nishi A, Kuroiwa M, Miller DB, O’Callaghan JP, Bateup HS, Shuto T, Sotogaku N, Fukuda T et al (2008) Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci 28(42):10460–10471. doi: 10.1523/JNEUROSCI.2518-08.2008 PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW (2004) Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 91(5):1025–1043. doi: 10.1111/j.1471-4159.2004.02797.x PubMedCrossRefGoogle Scholar
  69. 69.
    Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase: the initial step in norepinephrine biosynthesis. J Biol Chem 239:2910–2917PubMedGoogle Scholar
  70. 70.
    Yamashita N, Hayashi A, Baba J, Sawa A (1997) Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons. Jpn J Pharmacol 75(2):155–159PubMedCrossRefGoogle Scholar
  71. 71.
    Hulley P, Hartikka J, Lubbert H (1995) Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects them from the toxic effects of MPP+. J Neural Transm Suppl 46:217–228PubMedGoogle Scholar
  72. 72.
    Hulley P, Hartikka J, Abdel’Al S, Engels P, Buerki HR, Wiederhold KH, Muller T, Kelly P et al (1995) Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in substantia nigra neurons in vivo. Eur J Neurosci 7(12):2431–2440PubMedCrossRefGoogle Scholar
  73. 73.
    Yang L, Calingasan NY, Lorenzo BJ, Beal MF (2008) Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. Exp Neurol 211(1):311–314. doi: 10.1016/j.expneurol.2007.02.010 PubMedCrossRefGoogle Scholar
  74. 74.
    Casacchia M, Meco G, Castellana F, Bedini L, Cusimano G, Agnoli A (1983) Therapeutic use of a selective cAMP phosphodiesterase inhibitor (rolipram) in Parkinson’s disease. Pharmacol Res Commun 15(3):329–334PubMedCrossRefGoogle Scholar
  75. 75.
    Bloom TJ, Beavo JA (1996) Identification and tissue-specific expression of PDE7 phosphodiesterase splice variants. Proc Natl Acad Sci U S A 93(24):14188–14192PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109(3):366–398. doi: 10.1016/j.pharmthera.2005.07.003 PubMedCrossRefGoogle Scholar
  77. 77.
    Sasaki T, Kotera J, Omori K (2002) Novel alternative splice variants of rat phosphodiesterase 7B showing unique tissue-specific expression and phosphorylation. Biochem J 361(Pt 2):211–220PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Miro X, Perez-Torres S, Palacios JM, Puigdomenech P, Mengod G (2001) Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs. Synapse 40(3):201–214. doi: 10.1002/syn.1043 PubMedCrossRefGoogle Scholar
  79. 79.
    Reyes-Irisarri E, Perez-Torres S, Mengod G (2005) Neuronal expression of cAMP-specific phosphodiesterase 7B mRNA in the rat brain. Neuroscience 132(4):1173–1185. doi: 10.1016/j.neuroscience.2005.01.050 PubMedCrossRefGoogle Scholar
  80. 80.
    Sasaki T, Kotera J, Omori K (2004) Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. J Neurochem 89(2):474–483. doi: 10.1111/j.1471-4159.2004.02354.x PubMedCrossRefGoogle Scholar
  81. 81.
    Morales-Garcia JA, Aguilar-Morante D, Hernandez-Encinas E, Alonso-Gil S, Gil C, Martinez A, Santos A, Perez-Castillo A (2015) Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice. Neurobiol Aging 36(2):1160–1173. doi: 10.1016/j.neurobiolaging.2014.10.008 PubMedCrossRefGoogle Scholar
  82. 82.
    Morales-Garcia JA, Alonso-Gil S, Gil C, Martinez A, Santos A, Perez-Castillo A (2015) Phosphodiesterase 7 inhibition induces dopaminergic neurogenesis in hemiparkinsonian rats. Stem Cells Transl Med 4(6):564–575. doi: 10.5966/sctm.2014-0277 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Banerjee A, Patil S, Pawar MY, Gullapalli S, Gupta PK, Gandhi MN, Bhateja DK, Bajpai M et al (2012) Imidazopyridazinones as novel PDE7 inhibitors: SAR and in vivo studies in Parkinson’s disease model. Bioorg Med Chem Lett 22(19):6286–6291. doi: 10.1016/j.bmcl.2012.07.077 PubMedCrossRefGoogle Scholar
  84. 84.
    Perez DI, Pistolozzi M, Palomo V, Redondo M, Fortugno C, Gil C, Felix G, Martinez A et al (2012) 5-Imino-1,2-4-thiadiazoles and quinazolines derivatives as glycogen synthase kinase 3beta (GSK-3beta) and phosphodiesterase 7 (PDE7) inhibitors: determination of blood-brain barrier penetration and binding to human serum albumin. Eur J Pharm Sci 45(5):677–684. doi: 10.1016/j.ejps.2012.01.007 PubMedCrossRefGoogle Scholar
  85. 85.
    Bollen E, Prickaerts J (2012) Phosphodiesterases in neurodegenerative disorders. IUBMB Life 64(12):965–970. doi: 10.1002/iub.1104 PubMedCrossRefGoogle Scholar
  86. 86.
    Zhang HT (2010) Phosphodiesterase targets for cognitive dysfunction and schizophrenia—a New York Academy of Sciences meeting. IDrugs 13(3):166–168PubMedGoogle Scholar
  87. 87.
    Azuma R, Ishikawa K, Hirata K, Hashimoto Y, Takahashi M, Ishii K, Inaba A, Yokota T et al (2015) A novel mutation of PDE8B Gene in a Japanese family with autosomal-dominant striatal degeneration. Mov Disord 30(14):1964–1967. doi: 10.1002/mds.26345 PubMedCrossRefGoogle Scholar
  88. 88.
    Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K (1999) Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem 274(26):18438–18445PubMedCrossRefGoogle Scholar
  89. 89.
    Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon CE, Vardigan JD, Eddins D, Toolan DM et al (2013) The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology 64:215–223. doi: 10.1016/j.neuropharm.2012.06.013 PubMedCrossRefGoogle Scholar
  90. 90.
    Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C, Graf R, Langen B, Logue S et al (2009) Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther 331(2):574–590. doi: 10.1124/jpet.109.155994 PubMedCrossRefGoogle Scholar
  91. 91.
    Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA et al (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325(2):681–690. doi: 10.1124/jpet.107.132910 PubMedCrossRefGoogle Scholar
  92. 92.
    Nikiforuk A, Potasiewicz A, Rafa D, Drescher K, Bespalov A, Popik P (2016) The effects of PDE10 inhibition on attentional set-shifting do not depend on the activation of dopamine D1 receptors. Behav Pharmacol 27(4):331–338. doi: 10.1097/FBP.0000000000000201 PubMedCrossRefGoogle Scholar
  93. 93.
    Wilson JM, Ogden AM, Loomis S, Gilmour G, Baucum AJ 2nd, Belecky-Adams TL, Merchant KM (2015) Phosphodiesterase 10A inhibitor, MP-10 (PF-2545920), produces greater induction of c-Fos in dopamine D2 neurons than in D1 neurons in the neostriatum. Neuropharmacology 99:379–386. doi: 10.1016/j.neuropharm.2015.08.008 PubMedCrossRefGoogle Scholar
  94. 94.
    Diggle CP, Sukoff Rizzo SJ, Popiolek M, Hinttala R, Schulke JP, Kurian MA, Carr IM, Markham AF et al (2016) Biallelic mutations in PDE10A lead to loss of striatal PDE10A and a hyperkinetic movement disorder with onset in infancy. Am J Hum Genet 98(4):735–743. doi: 10.1016/j.ajhg.2016.03.015 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Cai Y, Miller CL, Nagel DJ, Jeon KI, Lim S, Gao P, Knight PA, Yan C (2011) Cyclic nucleotide phosphodiesterase 1 regulates lysosome-dependent type I collagen protein degradation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 31(3):616–623. doi: 10.1161/ATVBAHA.110.212621 PubMedCrossRefGoogle Scholar
  96. 96.
    Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V et al (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105(10):956–964. doi: 10.1161/CIRCRESAHA.109.198515 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Mery PF, Pavoine C, Pecker F, Fischmeister R (1995) Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. Mol Pharmacol 48(1):121–130PubMedGoogle Scholar
  98. 98.
    Bollen E, Akkerman S, Puzzo D, Gulisano W, Palmeri A, D’Hooge R, Balschun D, Steinbusch HW et al (2015) Object memory enhancement by combining sub-efficacious doses of specific phosphodiesterase inhibitors. Neuropharmacology 95:361–366. doi: 10.1016/j.neuropharm.2015.04.008 PubMedCrossRefGoogle Scholar
  99. 99.
    Wunder F, Gnoth MJ, Geerts A, Barufe D (2009) A novel PDE2A reporter cell line: characterization of the cellular activity of PDE inhibitors. Mol Pharm 6(1):326–336. doi: 10.1021/mp800127n PubMedCrossRefGoogle Scholar
  100. 100.
    Hidaka H, Hayashi H, Kohri H, Kimura Y, Hosokawa T, Igawa T, Saitoh Y (1979) Selective inhibitor of platelet cyclic adenosine monophosphate phosphodiesterase, cilostamide, inhibits platelet aggregation. J Pharmacol Exp Ther 211(1):26–30PubMedGoogle Scholar
  101. 101.
    Berk E, Christ T, Schwarz S, Ravens U, Knaut M, Kaumann AJ (2016) In permanent atrial fibrillation phosphodiesterase3 reduces force responses to 5-HT but neither PDE3 nor PDE4 influence abolished 5-HT-evoked arrhythmias. Br J Pharmacol. doi: 10.1111/bph.13525 PubMedPubMedCentralGoogle Scholar
  102. 102.
    Kauffman RF, Schenck KW, Utterback BG, Crowe VG, Cohen ML (1987) In vitro vascular relaxation by new inotropic agents: relationship to phosphodiesterase inhibition and cyclic nucleotides. J Pharmacol Exp Ther 242(3):864–872PubMedGoogle Scholar
  103. 103.
    Rodriguez-Ramos F, Gonzalez-Andrade M, Navarrete A (2011) Gnaphaliin A and B relax smooth muscle of guinea-pig trachea and rat aorta via phosphodiesterase inhibition. J Pharm Pharmacol 63(7):926–935. doi: 10.1111/j.2042-7158.2011.01275.x PubMedCrossRefGoogle Scholar
  104. 104.
    Nakano SJ, Nelson P, Sucharov CC, Miyamoto SD (2016) Myocardial response to milrinone in single right ventricle heart disease. J Pediatr. doi: 10.1016/j.jpeds.2016.04.009 PubMedPubMedCentralGoogle Scholar
  105. 105.
    Ahn HS, Eardley D, Watkins R, Prioli N (1986) Effects of several newer cardiotonic drugs on cardiac cyclic AMP metabolism. Biochem Pharmacol 35(7):1113–1121PubMedCrossRefGoogle Scholar
  106. 106.
    Sudo T, Tachibana K, Toga K, Tochizawa S, Inoue Y, Kimura Y, Hidaka H (2000) Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 59(4):347–356PubMedCrossRefGoogle Scholar
  107. 107.
    Woodrow MD, Ballantine SP, Barker MD, Clarke BJ, Dawson J, Dean TW, Delves CJ, Evans B et al (2009) Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration. Bioorg Med Chem Lett 19(17):5261–5265. doi: 10.1016/j.bmcl.2009.04.012 PubMedCrossRefGoogle Scholar
  108. 108.
    Richter W, Unciuleac L, Hermsdorf T, Kronbach T, Dettmer D (2001) Identification of inhibitor binding sites of the cAMP-specific phosphodiesterase 4. Cell Signal 13(4):287–297PubMedCrossRefGoogle Scholar
  109. 109.
    Drees M, Zimmermann R, Eisenbrand G (1993) 3′,5′-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. Cancer Res 53(13):3058–3061PubMedGoogle Scholar
  110. 110.
    Kuang R, Shue HJ, Blythin DJ, Shih NY, Gu D, Chen X, Schwerdt J, Lin L et al (2007) Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors. Bioorg Med Chem Lett 17(18):5150–5154. doi: 10.1016/j.bmcl.2007.06.092 PubMedCrossRefGoogle Scholar
  111. 111.
    Kuang R, Shue HJ, Xiao L, Blythin DJ, Shih NY, Chen X, Gu D, Schwerdt J et al (2012) Discovery of oxazole-based PDE4 inhibitors with picomolar potency. Bioorg Med Chem Lett 22(7):2594–2597. doi: 10.1016/j.bmcl.2012.01.115 PubMedCrossRefGoogle Scholar
  112. 112.
    Padma-Nathan H, McMurray JG, Pullman WE, Whitaker JS, Saoud JB, Ferguson KM, Rosen RC (2001) On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 13(1):2–9. doi: 10.1038/sj.ijir.3900631 PubMedCrossRefGoogle Scholar
  113. 113.
    Xu Z, Yang B, Zhang J, Zheng J (2016) The regulation of sGC on the rat model of neuropathic pain is mediated by 5-HT1ARs and NO/cGMP pathway. Am J Transl Res 8(2):1027–1036PubMedPubMedCentralGoogle Scholar
  114. 114.
    Saenz de Tejada I, Angulo J, Cuevas P, Fernandez A, Moncada I, Allona A, Lledo E, Korschen HG et al (2001) The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res 13(5):282–290PubMedCrossRefGoogle Scholar
  115. 115.
    Doh H, Shin CY, Son M, Ko JI, Yoo M, Kim SH, Kim WB (2002) Mechanism of erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159. Arch Pharm Res 25(6):873–878PubMedCrossRefGoogle Scholar
  116. 116.
    Cote RH (2004) Characteristics of photoreceptor PDE (PDE6): similarities and differences to PDE5. Int J Impot Res 16(Suppl 1):S28–S33. doi: 10.1038/sj.ijir.3901212 PubMedCrossRefGoogle Scholar
  117. 117.
    Zhang X, Feng Q, Cote RH (2005) Efficacy and selectivity of phosphodiesterase-targeted drugs in inhibiting photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors. Invest Ophthalmol Vis Sci 46(9):3060–3066. doi: 10.1167/iovs.05-0257 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Smith SJ, Cieslinski LB, Newton R, Donnelly LE, Fenwick PS, Nicholson AG, Barnes PJ, Barnette MS et al (2004) Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: in vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol Pharmacol 66(6):1679–1689. doi: 10.1124/mol.104.002246 PubMedCrossRefGoogle Scholar
  119. 119.
    Goto M, Kadoshima-Yamaoka K, Murakawa M, Yoshioka R, Tanaka Y, Inoue H, Murafuji H, Kanki S et al (2010) Phosphodiesterase 7A inhibitor ASB16165 impairs proliferation of keratinocytes in vitro and in vivo. Eur J Pharmacol 633(1–3):93–97. doi: 10.1016/j.ejphar.2010.01.024 PubMedCrossRefGoogle Scholar
  120. 120.
    DeNinno MP, Wright SW, Visser MS, Etienne JB, Moore DE, Olson TV, Rocke BN, Andrews MP et al (2011) 1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability. Bioorg Med Chem Lett 21(10):3095–3098. doi: 10.1016/j.bmcl.2011.03.022 PubMedCrossRefGoogle Scholar
  121. 121.
    Tsai LC, Beavo JA (2012) Regulation of adrenal steroidogenesis by the high-affinity phosphodiesterase 8 family. Horm Metab Res 44(10):790–794. doi: 10.1055/s-0032-1321861 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M (2005) Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol 68(6):1775–1781. doi: 10.1124/mol.105.017608 PubMedGoogle Scholar
  123. 123.
    Hayashi S, Ozawa H (1975) Antispasmodic action of 1-diethylaminoethyl-3-(p-methoxybenzyl)-2-quinoxalone (P 201-1) and its inhibitory effect on cyclic 3′,5′-nucleotide phosphodiesterase (PDE) activity. Chem Pharm Bull (Tokyo) 23(4):810–816Google Scholar
  124. 124.
    Berndt SF, Schulz HU, Stock K (1976) Influence of papaverine derivatives on phosphodiesterase activity, cyclic 3′,5′-AMP levels and relaxing effect on rabbit ileum. Naunyn Schmiedeberg’s Arch Pharmacol 294(3):271–275CrossRefGoogle Scholar
  125. 125.
    Ceyhan O, Birsoy K, Hoffman CS (2012) Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen. Chem Biol 19(1):155–163. doi: 10.1016/j.chembiol.2011.12.010 PubMedCrossRefGoogle Scholar
  126. 126.
    Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59(4):675–680PubMedCrossRefGoogle Scholar
  127. 127.
    Mantamadiotis T, Lemberger T, Bleckmann SC, Kern H, Kretz O, Martin Villalba A, Tronche F, Kellendonk C et al (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31(1):47–54. doi: 10.1038/ng882 PubMedCrossRefGoogle Scholar
  128. 128.
    Finkbeiner S (2000) CREB couples neurotrophin signals to survival messages. Neuron 25(1):11–14PubMedCrossRefGoogle Scholar
  129. 129.
    Chalovich EM, Zhu JH, Caltagarone J, Bowser R, Chu CT (2006) Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J Biol Chem 281(26):17870–17881. doi: 10.1074/jbc.M602632200 PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Engele J, Franke B (1996) Effects of glial cell line-derived neurotrophic factor (GDNF) on dopaminergic neurons require concurrent activation of cAMP-dependent signaling pathways. Cell Tissue Res 286(2):235–240PubMedCrossRefGoogle Scholar
  131. 131.
    Nam JH, Leem E, Jeon MT, Jeong KH, Park JW, Jung UJ, Kholodilov N, Burke RE et al (2015) Induction of GDNF and BDNF by hRheb(S16H) transduction of SNpc neurons: neuroprotective mechanisms of hRheb(S16H) in a model of Parkinson’s disease. Mol Neurobiol 51(2):487–499. doi: 10.1007/s12035-014-8729-2 PubMedCrossRefGoogle Scholar
  132. 132.
    Goldberg JL, Barres BA (2000) The relationship between neuronal survival and regeneration. Annu Rev Neurosci 23:579–612. doi: 10.1146/annurev.neuro.23.1.579 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Dominic Ngima Nthenge-Ngumbau
    • 1
  • Kochupurackal P. Mohanakumar
    • 1
    Email author
  1. 1.Inter University Centre for Biomedical Research and Super Speciality HospitalMahatma Gandhi University Campus at ThalappadyKottayamIndia

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