Current Neurology and Neuroscience Reports

, Volume 12, Issue 4, pp 376–385 | Cite as

Adenosine A2A Antagonists in Parkinson’s Disease: What’s Next?

Movement Disorders (SA Factor, Section Editor)

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, affecting up to 10 million people worldwide. Current treatment primarily involves symptom management with dopaminergic replacement therapy. Levodopa remains the most effective oral treatment, although long-term use is associated with complications such as wearing off, dyskinesias, and on-off fluctuations. Non-dopaminergic medications that improve PD symptoms and motor fluctuations are in demand. Adenosine A2A receptors are abundantly expressed within the basal ganglia and offer a unique target to modify abnormal striatal signaling associated with PD. Preclinical animal models have shown the ability of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor fluctuations and dyskinesia, as well as protect against toxin-induced neuronal degeneration. Both istradefylline and preladenant have demonstrated moderate efficacy in reducing off time in PD patients with motor fluctuations. The safety and efficacy of this class of compounds continues to be defined and future studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.

Keywords

Parkinson’s disease Adenosine Adenosine antagonists A2A Dyskinesias Motor fluctuations Neuroprotection Istradefylline Preladenant SYN115 

References

Papers of particular interest, published recently, have been highlighted as: •  Of importance •• Of major importance

  1. 1.
    Stacy M. Medical treatment of Parkinson disease. Neurol Clin. 2009;27(3):605–31. v.PubMedCrossRefGoogle Scholar
  2. 2.
    Lewitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med. 2008;359(23):2468–76.PubMedCrossRefGoogle Scholar
  3. 3.
    Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989;12(10):366–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci. 2006;29(11):647–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol. 2007;83(5):277–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Daly JW, Butts-Lamb P, Padgett W. Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell Mol Neurobiol. 1983;3(1):69–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Schiffmann SN, Jacobs O, Vanderhaeghen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J Neurochem. 1991;57(3):1062–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Rosin DL, Robeva A, Woodard RL, Guyenet PG, Linden J. Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol. 1998;401(2):163–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Morelli M, Carta AR, Kachroo A, Schwarzschild MA. Pathophysiological roles for purines: adenosine, caffeine and urate. Prog Brain Res. 2010;183:183–208.PubMedCrossRefGoogle Scholar
  11. 11.
    Augood SJ, Emson PC. Adenosine A2a receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study. Brain Res Mol Brain Res. 1994;22(1–4):204–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Hettinger BD, Lee A, Linden J, Rosin DL. Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. J Comp Neurol. 2001;431(3):331–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Kurokawa M, Koga K, Kase H, Nakamura J, Kuwana Y. Adenosine A2a receptor-mediated modulation of striatal acetylcholine release in vivo. J Neurochem. 1996;66(5):1882–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Annu Rev Neurosci. 1992;15:285–320.PubMedCrossRefGoogle Scholar
  15. 15.
    Ochi M, Shiozaki S, Kase H. Adenosine A(2A) receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson’s disease. Neuroscience. 2004;127(1):223–31.PubMedCrossRefGoogle Scholar
  16. 16.
    Shindou T, Richardson PJ, Mori A, Kase H, Ichimura M. Adenosine modulates the striatal GABAergic inputs to the globus pallidus via adenosine A2A receptors in rats. Neurosci Lett. 2003;352(3):167–70.PubMedCrossRefGoogle Scholar
  17. 17.
    DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 1990;13(7):281–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Obeso JA, Lanciego JL. Past, present, and future of the pathophysiological model of the Basal Ganglia. Front Neuroanat. 2011;5:39.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferré S, Borycz J, Goldberg SR, Hope BT, Morales M, Lluis C, et al. Role of adenosine in the control of homosynaptic plasticity in striatal excitatory synapses. J Integr Neurosci. 2005;4(4):445–64.PubMedCrossRefGoogle Scholar
  20. 20.
    Newman EA. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 2003;26(10):536–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Hertz L, Zielke HR. Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci. 2004;27(12):735–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Mori A, Shindou T. Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists. Neurology. 2003;61(11 Suppl 6):S44–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Ferré S, Rubio A, Fuxe K. Stimulation of adenosine A2 receptors induces catalepsy. Neurosci Lett. 1991;130(2):162–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Kanda T, Shiozaki S, Shimada J, Suzuki F, Nakamura J. KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity. Eur J Pharmacol. 1994;256(3):263–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Kanda T, Tashiro T, Kuwana Y, Jenner P. Adenosine A2A receptors modify motor function in MPTP-treated common marmosets. Neuroreport. 1998a;9(12):2857–60.CrossRefGoogle Scholar
  26. 26.
    Shiozaki S, Ichikawa S, Nakamura J, Kitamura S, Yamada K, Kuwana Y. Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP. Psychopharmacology (Berl). 1999;147(1):90–5.CrossRefGoogle Scholar
  27. 27.
    Hauber W, Neuscheler P, Nagel J, Müller CE. Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A(2A) receptors in the caudate-putamen of rats. Eur J Neurosci. 2001;14(8):1287–93.PubMedCrossRefGoogle Scholar
  28. 28.
    Rose S, Ramsay Croft N, Jenner P. The novel adenosine A2a antagonist ST1535 potentiates the effects of a threshold dose of l-dopa in unilaterally 6-OHDA-lesioned rats. Brain Res. 2007;1133(1):110–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Wardas J, Konieczny J, Lorenc-Koci E. SCH 58261, an A(2A) adenosine receptor antagonist, counteracts parkinsonian-like muscle rigidity in rats. Synapse. 2001;41(2):160–71.PubMedCrossRefGoogle Scholar
  30. 30.
    Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4–2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7 H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression. J Pharmacol Exp Ther. 2009;330(1):294–303.PubMedCrossRefGoogle Scholar
  31. 31.
    Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998(b) Apr;43(4):507–13.Google Scholar
  32. 32.
    Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, et al. Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Exp Neurol. 2000;162(2):321–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Hodgson RA, Bedard PJ, Varty GB, Kazdoba TM, Di Paolo T, Grzelak ME, et al. Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders. Exp Neurol. 2010;225(2):384–90.PubMedCrossRefGoogle Scholar
  34. 34.
    Halldner L, Lozza G, Lindström K, Fredholm BB. Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist. Eur J Pharmacol. 2000;406(3):345–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Pinna A, Fenu S, Morelli M. Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats. Synapse. 2001;39(3):233–8.CrossRefGoogle Scholar
  36. 36.
    Jenner P. A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD. Neurology. 2003;61(11 Suppl 6):S32–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Simola N, Fenu S, Baraldi PG, Tabrizi MA, Morelli M. Blockade of adenosine A2A receptors antagonizes parkinsonian tremor in the rat tacrine model by an action on specific striatal regions. Exp Neurol. 2004;189(1):182–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Correa M, Wisniecki A, Betz A, Dobson DR, O’Neill MF, O’Neill MJ, et al. The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism. Behav Brain Res. 2004;148(1–2):47–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Pinna A, Corsi C, Carta AR, Valentini V, Pedata F, Morelli M. Modification of adenosine extracellular levels and adenosine A(2A) receptor mRNA by dopamine denervation. Eur J Pharmacol. 2002;446(1–3):75–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Koga K, Kurokawa M, Ochi M, Nakamura J, Kuwana Y. Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-Parkinsonian rats. Eur J Pharmacol. 2000;408(3):249–55.PubMedCrossRefGoogle Scholar
  41. 41.
    Tronci E, Simola N, Borsini F, Schintu N, Frau L, Carminati P, et al. Characterization of the antiparkinsonian effects of the new adenosine A2A receptor antagonist ST1535: acute and subchronic studies in rats. Eur J Pharmacol. 2007;566(1–3):94–102.PubMedCrossRefGoogle Scholar
  42. 42.
    Fredduzzi S, Moratalla R, Monopoli A, Cuellar B, Xu K, Ongini E, et al. Persistent behavioral sensitization to chronic L-DOPA requires A2A adenosine receptors. J Neurosci. 2002;22(3):1054–62.PubMedGoogle Scholar
  43. 43.
    Xiao D, Bastia E, Xu YH, Benn CL, Cha JH, Peterson TS, et al. Forebrain adenosine A2A receptors contribute to L-3,4-dihydroxyphenylalanine-induced dyskinesia in hemiparkinsonian mice. J Neurosci. 2006;26(52):13548–55.PubMedCrossRefGoogle Scholar
  44. 44.
    Bastia E, Xu YH, Scibelli AC, Day YJ, Linden J, Chen JF, et al. A crucial role for forebrain adenosine A(2A) receptors in amphetamine sensitization. Neuropsychopharmacology. 2005;30(5):891–900.PubMedCrossRefGoogle Scholar
  45. 45.
    Bibbiani F, Oh JD, Petzer JP, Castagnoli Jr N, Chen JF, Schwarzschild MA, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol. 2003;184(1):285–94.PubMedCrossRefGoogle Scholar
  46. 46.
    Lundblad M, Vaudano E, Cenci MA. Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia. J Neurochem. 2003;84(6):1398–410.PubMedCrossRefGoogle Scholar
  47. 47.
    Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple dose pharma- cokinetics of istradephylline in healthy subjects. Clin Pharmacol Ther. 2005a;83(Suppl):PIII-89Google Scholar
  48. 48.
    Rao N, Uchimura T, Mori A. Evaluation of safety, tolerability, and multiple dose pharmacokinetics of istradephylline in Parkinson’s disease patients. Clin Pharmacol Ther. 2005b;83(Suppl):PIII-88Google Scholar
  49. 49.
    Brooks DJ, Doder M, Osman S, Luthra SK, Hirani E, Hume S, et al. Positron emission tomography analysis of [11 C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse. 2008;62(9):671–81.PubMedCrossRefGoogle Scholar
  50. 50.
    Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F, Gillespie M, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Hauser RA, Hubble JP, Truong DD. Istradefylline US-001 Study Group. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology. 2003;61(3):297–303.PubMedCrossRefGoogle Scholar
  52. 52.
    LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P, et al. 6002-US-005 Study Group. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol. 2008;63(3):295–302.PubMedCrossRefGoogle Scholar
  53. 53.
    Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology. 2008;70(23):2233–40.PubMedCrossRefGoogle Scholar
  54. 54.
    •• Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M. Japanese Istradefylline Study Group. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord. 2010;25(10):1437–43. A randomized trial of istradefylline in levodopa-treated PD subjects, which showed a reduction in off time as well as improvement in motor function. In contrast to previous clinical studies, these findings were more consistent with the effects demonstrated in animal models.PubMedCrossRefGoogle Scholar
  55. 55.
    Factor S, Mark MH, Watts R, Struck L, Mori A, Ballerini R, et al. Istradefylline 6002-US-007 Study Group. A long-term study of istradefylline in subjects with fluctuating Parkinson’s disease. Parkinsonism Relat Disord. 2010;16(6):423–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R, et al. Istradefylline 6002-US-013 Study Group. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord. 2008;23(15):2177–85.PubMedCrossRefGoogle Scholar
  57. 57.
    Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: Results of the KW-6002-US-018 study. Parkinsonism Relat Disord. 2011 Oct 12.Google Scholar
  58. 58.
    • Fernandez HH, Greeley DR, Zweig RM, Wojcieszek J, Mori A, Sussman NM. 6002-US-051 Study Group. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16–20. A randomized trial of istradefylline as monotherapy in early PD subjects showed no significant difference in UPDRS change compared to placebo at 12 weeks. These results differ from those seen in animal models and have cautioned the expectations of A2A antagonists as monotherapy in PD.PubMedCrossRefGoogle Scholar
  59. 59.
    FDA Issues Not Approvable Letter for Istradefylline. http://www.drugs.com/nda/kw_6002_080228.html.
  60. 60.
    •• Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol. 2011;10(3):221–9. The first clinical trial of preladenant in PD patients showed a significant reduction in off time and was well tolerated. Future studies in advanced as well as untreated PD patients are underway.PubMedCrossRefGoogle Scholar
  61. 61.
    •• Black KJ, Koller JM, Campbell MC, Gusnard DA, Bandak SI. Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci. 2010;30(48):16284–92. MRI study of SYN115 demonstrating reduced thalamic blood flow and supporting its clinical effect on basal ganglia activity. A phase II study in levodopa-treated PD subjects with motor fluctuations is underway.PubMedCrossRefGoogle Scholar
  62. 62.
    Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. 2000;283(20):2674–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Ascherio A, Zhang SM, Hernán MA, Kawachi I, Colditz GA, Speizer FE, et al. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol. 2001;50(1):56–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Hancock DB, Martin ER, Stajich JM, Jewett R, Stacy MA, Scott BL, et al. Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson disease. Arch Neurol. 2007;64(4):576–80.PubMedCrossRefGoogle Scholar
  65. 65.
    Hu G, Bidel S, Jousilahti P, Antikainen R, Tuomilehto J. Coffee and tea consumption and the risk of Parkinson’s disease. Mov Disord. 2007;22(15):2242–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Sääksjärvi K, Knekt P, Rissanen H, Laaksonen MA, Reunanen A, Männistö S. Prospective study of coffee consumption and risk of Parkinson’s disease. Eur J Clin Nutr. 2008;62(7):908–15.PubMedCrossRefGoogle Scholar
  67. 67.
    Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci. 2001;21(10):RC143.PubMedGoogle Scholar
  68. 68.
    Ikeda K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson’s disease. J Neurochem. 2002;80(2):262–70.PubMedCrossRefGoogle Scholar
  69. 69.
    Xu K, Xu YH, Chen JF, Schwarzschild MA. Caffeine’s neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice. Neurosci Lett. 2002;322(1):13–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Yu L, Shen HY, Coelho JE, Araújo IM, Huang QY, Day YJ, et al. Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Ann Neurol. 2008;63(3):338–46.PubMedCrossRefGoogle Scholar
  71. 71.
    Fiebich BL, Biber K, Lieb K, van Calker D, Berger M, Bauer J, et al. Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia. 1996;18(2):152–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Saura J, Angulo E, Ejarque A, Casadó V, Tusell JM, Moratalla R, et al. Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia. J Neurochem. 2005;95(4):919–29.PubMedCrossRefGoogle Scholar
  73. 73.
    • Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology. 2011;76(21):1811–6. A PET study demonstrating increased A2A receptor availability in PD patients with LIDs. The findings support a potential role for A2A antagonists in both the prevention and treatment of this motor complication.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Duke University Medical CenterDurhamUSA

Personalised recommendations