Protective Agents in Parkinson's Disease: Caffeine and Adenosine A2A Receptor Antagonists

  • Nicola Simola
  • Annalisa Pinna
  • Lucia Frau
  • Micaela Morelli
Reference work entry

Abstract

The pharmacologic management of Parkinson’s disease is based on drugs that act on the motor symptoms, whereas there are currently no drugs available that can alter the progressive neurodegeneration of dopaminergic neurons. Based on recent findings suggesting that the adenosinergic system is one of the most interesting in the field of neuroprotection in Parkinson’s disease, this chapter describes the functions of adenosine and its receptors in the central nervous system, with particular emphasis on their role in neurotoxicity/neuroprotection. Results of epidemiologic surveys demonstrating that intake of caffeine, an adenosine A1/A2A receptor antagonist, is inversely correlated with Parkinson’s disease are summarized. Moreover, evidence originating from preclinical studies showing that the antagonism of the adenosine A2A receptor is responsible for the neuroprotective effects of caffeine is also presented. This chapter therefore provides a comprehensive analysis of the current literature concerning the adenosinergic-based neuroprotective intervention strategy for Parkinson’s disease.

Keywords

Attenuation Estrogen Dopamine Adenosine Interferon 

Notes

Acknowledgments

Dr. Nicola Simola gratefully acknowledges Sardinia Regional Government for the financial support (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007–2013 - Axis IV Human Resources, Objective l.3, Line of Activity l.3.1 “Avviso di chiamata per il finanziamento di Assegni di Ricerca”). Dr. Lucia Frau is supported by Regione Autonoma della Sardegna (Legge Regionale 7 Agosto 2007, N.7, annualità 2010).

References

  1. Aguiar, L. M., Nobre, H. V., Jr., Macêdo, D. S., Oliveira, A. A., Freitas, R. M., Vasconcelos, S. M., Cunha, G. M., Sousa, F. C., & Viana, G. S. (2006). Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats. Pharmacology, Biochemistry, and Behavior, 84, 415–419.PubMedCrossRefGoogle Scholar
  2. Alfinito, P. D., Wang, S. P., Manzino, L., Rijhsinghani, S., Zeevalk, G. D., & Sonsalla, P. K. (2003). Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively. Journal of Neuroscience, 23, 10982–10987.PubMedGoogle Scholar
  3. Armentero, M. T., Fancellu, R., Nappi, G., Bramanti, P., & Blandini, F. (2006). Prolonged blockade of NMDA or mGluR5 glutamate receptors reduces nigrostriatal degeneration while inducing selective metabolic changes in the basal ganglia circuitry in a rodent model of Parkinson’s disease. Neurobiology of Disease, 22, 1–9.PubMedCrossRefGoogle Scholar
  4. Armentero, M. T., Pinna, A., Ferré, S., Lanciego, J. L., Müller, C. E., & Franco, R. (2011). Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacology and Therapeutics, 132, 280–299.PubMedCentralPubMedCrossRefGoogle Scholar
  5. Ascherio, A., Zhang, S. M., Hernán, M. A., Kawachi, I., Colditz, G. A., Speizer, F. E., & Willett, W. C. (2001). Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Annals of Neurology, 50, 56–63.PubMedCrossRefGoogle Scholar
  6. Ascherio, A., Chen, H., Schwarzschild, M. A., Zhang, S. M., Colditz, G. A., & Speizer, F. E. (2003). Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology, 60, 790–795.PubMedCrossRefGoogle Scholar
  7. Ascherio, A., Weisskopf, M. G., O’Reilly, E. J., McCullough, M. L., Calle, E. E., Rodriguez, C., & Thun, M. J. (2004). Coffee consumption, gender, and Parkinson’s disease mortality in the cancer prevention study II cohort: The modifying effects of estrogen. American Journal of Epidemiology, 160, 977–984.PubMedCrossRefGoogle Scholar
  8. Benedetti, M. D., Bower, J. H., Maraganore, D. M., McDonnell, S. K., Peterson, B. J., Ahlskog, J. E., Schaid, D. J., & Rocca, W. A. (2000). Smoking, alcohol, and coffee consumption preceding Parkinson’s disease: A case–control study. Neurology, 55, 1350–1358.PubMedCrossRefGoogle Scholar
  9. Blandini, F., Nappi, G., & Greenamyre, J. T. (2001). Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson’s disease. Annals of Neurology, 49, 525–529.PubMedCrossRefGoogle Scholar
  10. Bogenpohl, J. W., Ritter, S. L., Hall, R. A., & Smith, Y. (2012). Adenosine A(2A) receptor in the monkey basal ganglia: Ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum. The Journal of Comparative Neurology, 520, 570–589.PubMedCentralPubMedCrossRefGoogle Scholar
  11. Brothers, H. M., Marchalant, Y., & Wenk, G. L. (2010). Caffeine attenuates lipopolysaccharide-induced neuroinflammation. Neuroscience Letters, 480, 97–100.PubMedCentralPubMedCrossRefGoogle Scholar
  12. Carta, A. R., Kachroo, A., Schintu, N., Xu, K., Schwarzschild, M. A., Wardas, J., & Morelli, M. (2009). Inactivation of neuronal forebrain a receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease. Journal of Neurochemistry, 111, 1478–1489.PubMedCentralPubMedCrossRefGoogle Scholar
  13. Carvalho, G. A., & Nikkhah, G. (2001). Subthalamic nucleus lesions are neuroprotective against terminal 6-OHDA-induced striatal lesions and restore postural balancing reactions. Experimental Neurology, 171, 405–417.PubMedCrossRefGoogle Scholar
  14. Cauli, O., & Morelli, M. (2005). Caffeine and the dopaminergic system. Behavioural Pharmacology, 16, 63–77.PubMedCrossRefGoogle Scholar
  15. Chen, J. F., Xu, K., Petzer, J. P., Staal, R., Xu, Y. H., Beilstein, M., Sonsalla, P. K., Castagnoli, K., Castagnoli, N., Jr., & Schwarzschild, M. A. (2001). Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. Journal of Neuroscience, 21, RC143.PubMedGoogle Scholar
  16. Costa, J., Lunet, N., Santos, C., Santos, J., & Vaz-Carneiro, A. (2010). Caffeine exposure and the risk of Parkinson’s disease: A systematic review and meta-analysis of observational studies. Journal of Alzheimer’s Disease, 20, S221–S238.PubMedGoogle Scholar
  17. Cunha, R. A. (2001). Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: Different roles, different sources and different receptors. Neurochemistry International, 38, 107–125.PubMedCrossRefGoogle Scholar
  18. de Rijk, M. C., Launer, L. J., Berger, K., Breteler, M. M., Dartigues, J. F., Baldereschi, M., Fratiglioni, L., Lobo, A., Martinez-Lage, J., Trenkwalder, C., & Hofman, A. (2000). Prevalence of Parkinson’s disease in Europe: A collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology, 54, S21–S23.PubMedGoogle Scholar
  19. Delle Donne, K. T., & Sonsalla, P. K. (1994). Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. Journal of Pharmacology and Experimental Therapeutics, 271, 1320–1326.PubMedGoogle Scholar
  20. Dunwiddie, T. V., & Masino, S. A. (2001). The role and regulation of adenosine in the central nervous system. Annual Review of Neuroscience, 24, 31–55.PubMedCrossRefGoogle Scholar
  21. Ferre, S., Fredholm, B. B., Morelli, M., Popoli, P., & Fuxe, K. (1997). Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends in Neurosciences, 20, 482–487.PubMedCrossRefGoogle Scholar
  22. Floran, B., Gonzalez, B., Florán, L., Erlij, D., & Aceves, J. (2005). Interactions between adenosine A(2A) and dopamine D2 receptors in the control of [(3)H]GABA release in the globus pallidus of the rat. European Journal of Pharmacology, 520, 43–50.PubMedCrossRefGoogle Scholar
  23. Frau, L., Borsini, F., Wardas, J., Khairnar, A. S., Schintu, N., & Morelli, M. (2011). Neuroprotective and anti-inflammatory effects of the adenosine A(2A) receptor antagonist ST1535 in a MPTP mouse model of Parkinson’s disease. Synapse, 65, 181–188.PubMedCrossRefGoogle Scholar
  24. Fredholm, B. B., Bättig, K., Holmén, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews, 51, 83–133.PubMedGoogle Scholar
  25. Fredholm, B. B., Chen, J. F., Cunha, R. A., Svenningsson, P., & Vaugeois, J. M. (2005). Adenosine and brain function. International Review of Neurobiology, 63, 191–270.PubMedCrossRefGoogle Scholar
  26. Gerevich, Z., Wirkner, K., & Illes, P. (2002). Adenosine A2A receptors inhibit the N-methyl-D-aspartate component of excitatory synaptic currents in rat striatal neurons. European Journal of Pharmacology, 451, 161–164.PubMedCrossRefGoogle Scholar
  27. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell, 140, 918–934.PubMedCentralPubMedCrossRefGoogle Scholar
  28. Green, T. A., & Schenk, S. (2002). Dopaminergic mechanism for caffeine-produced cocaine seeking in rats. Neuropsychopharmacology, 26, 422–430.PubMedCrossRefGoogle Scholar
  29. Greenamyre, J. T. (2001). Glutamatergic influences on the basal ganglia. Clinical Neuropharmacology, 24, 65–70.PubMedCrossRefGoogle Scholar
  30. Halliday, G. M., & Stevens, C. H. (2011). Glia: Initiators and progressors of pathology in Parkinson’s disease. Movement Disorders, 26, 6–17.PubMedCrossRefGoogle Scholar
  31. Halperin, I., Morelli, M., Korczyn, A. D., Youdim, M. B., & Mandel, S. A. (2009). Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimer’s and Parkinson’s diseases. Neurotherapeutics, 6, 128–140.PubMedCrossRefGoogle Scholar
  32. Hauser, R. A., & Schwarzschild, M. A. (2005). Adenosine A(2A) receptor antagonists for Parkinson’s disease: Rationale, therapeutic potential and clinical experience. Drugs & Aging, 22, 471–482.CrossRefGoogle Scholar
  33. Hettinger, B. D., Lee, A., Linden, J., & Rosin, D. L. (2001). Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. The Journal of Comparative Neurology, 431, 331–346.PubMedCrossRefGoogle Scholar
  34. Hirsch, E. C., & Hunot, S. (2009). Neuroinflammation in Parkinson’s disease: A target for neuroprotection? Lancet Neurology, 8, 382–397.PubMedCrossRefGoogle Scholar
  35. Hu, G., Bidel, S., Jousilahti, P., Antikainen, R., & Tuomilehto, J. (2007). Coffee and tea consumption and the risk of Parkinson’s disease. Movement Disorders, 22, 2242–2248.PubMedCrossRefGoogle Scholar
  36. Jellinger, K. A. (1991). Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Molecular and Chemical Neuropathology, 14, 153–197.PubMedCrossRefGoogle Scholar
  37. Jones, C. K., Bubser, M., Thompson, A. D., Dickerson, J. W., Turle-Lorenzo, N., Amalric, M., Blobaum, A. L., Bridges, T. M., Morrison, R. D., Jadhav, S., Engers, D. W., Italiano, K., Bode, J., Daniels, J. S., Lindsley, C. W., Hopkins, C. R., Conn, P. J., & Niswender, C. M. (2012). The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson’s disease. Journal of Pharmacology and Experimental Therapeutics, 340, 404–421.PubMedCentralPubMedCrossRefGoogle Scholar
  38. Kachroo, A., Irizarry, M. C., & Schwarzschild, M. A. (2010). Caffeine protects against combined paraquat and maneb-induced dopaminergic neuron degeneration. Experimental Neurology, 223, 657–661.PubMedCentralPubMedCrossRefGoogle Scholar
  39. Kelsey, J. E., Langelier, N. A., Oriel, B. S., & Reedy, C. (2009). The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A(2A) and A(1) antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat. Psychopharmacology, 201, 529–539.PubMedCrossRefGoogle Scholar
  40. Khairnar, A., Plumitallo, A., Frau, L., Schintu, N., & Morelli, M. (2010). Caffeine enhances astroglia and microglia reactivity induced by 3,4-methylenedioxymethamphetamine (‘ecstasy’) in mouse brain. Neurotoxicity Research, 17, 435–439.PubMedCrossRefGoogle Scholar
  41. Kurokawa, M., Koga, K., Kase, H., Nakamura, J., & Kuwana, Y. (1996). Adenosine A(2A) receptor-mediated modulation of striatal acetylcholine release in vivo. Journal of Neurochemistry, 66, 1882–1888.PubMedCrossRefGoogle Scholar
  42. Lancelot, E., & Beal, M. F. (1998). Glutamate toxicity in chronic neurodegenerative disease. Progress in Brain Research, 116, 331–347.PubMedCrossRefGoogle Scholar
  43. Litteljohn, D., Mangano, E., Clarke, M., Bobyn, J., Moloney, K., & Hayley, S. (2010). Inflammatory mechanisms of neurodegeneration in toxin-based models of Parkinson’s disease. Parkinsons Dis. 30, 2011:713517.Google Scholar
  44. Lopes, L. V., Sebastião, A. M., & Ribeiro, J. A. (2011). Adenosine and related drugs in brain diseases: Present and future in clinical trials. Current Topics in Medicinal Chemistry, 11, 1087–1101.PubMedCrossRefGoogle Scholar
  45. Łukasiewicz, S., Błasiak, E., Faron-Górecka, A., Polit, A., Tworzydło, M., Górecki, A., Wasylewski, Z., & Dziedzicka-Wasylewska, M. (2007). Fluorescence studies of homooligomerization of adenosine A(2A) and serotonin 5-HT(1A) receptors reveal the specificity of receptor interactions in the plasma membrane. Pharmacological Reports, 59, 379–392.PubMedGoogle Scholar
  46. Melani, A., Pantoni, L., Bordoni, F., Gianfriddo, M., Bianchi, L., Vannucchi, M. G., Bertorelli, R., Monopoli, A., & Pedata, F. (2003). The selective A(2A) receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Research, 959, 243–250.PubMedCrossRefGoogle Scholar
  47. Mitchell, H. L., Frisella, W. A., Brooker, R. W., & Yoon, K. W. (1995). Attenuation of traumatic cell death by an adenosine A(1) agonist in rat hippocampal cells. Neurosurgery, 36, 1003–1008.PubMedCrossRefGoogle Scholar
  48. Morelli, M., Carta, A. R., Kachroo, A., & Schwarzschild, M. A. (2010). Pathophysiological roles for purines: Adenosine, caffeine and urate. Progress in Brain Research, 183, 183–208.PubMedCentralPubMedCrossRefGoogle Scholar
  49. Nakaso, K., Ito, S., & Nakashima, K. (2008). Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell death in a Parkinson’s disease model of SH-SY5Y cells. Neuroscience Letters, 432, 146–150.PubMedCrossRefGoogle Scholar
  50. Nobre, H. V., Jr., Cunha, G. M., de Vasconcelos, L. M., Magalhães, H. I., Oliveira Neto, R. N., Maia, F. D., de Moraes, M. O., Leal, L. K., & Viana, G. S. (2010). Caffeine and CSC, adenosine A(2A) antagonists, offer neuroprotection against 6-OHDA-induced neurotoxicity in rat mesencephalic cells. Neurochemistry International, 56, 51–58.PubMedCrossRefGoogle Scholar
  51. Peterson, J. D., Goldberg, J. A., & Surmeier, D. J. (2012). Adenosine A(2A) receptor antagonists attenuate striatal adaptations following dopamine depletion. Neurobiology of Disease, 45, 409–416.PubMedCentralPubMedCrossRefGoogle Scholar
  52. Phillips, A. G., Vacca, G., & Ahn, S. (2008). A top-down perspective on dopamine, motivation and memory. Pharmacology, Biochemistry, and Behavior, 90, 236–249.PubMedCrossRefGoogle Scholar
  53. Piallat, B., Benazzouz, A., & Benabid, A. L. (1996). Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: Behavioural and immunohistochemical studies. European Journal of Neuroscience, 8, 1408–1414.PubMedCrossRefGoogle Scholar
  54. Poewe, W. (2008). Non-motor symptoms in Parkinson’s disease. European Journal of Neurology, 15, 14–20.PubMedCrossRefGoogle Scholar
  55. Popoli, P., Betto, P., Reggio, R., & Ricciarello, G. (1995). Adenosine A(2A) receptor stimulation enhances striatal extracellular glutamate levels in rats. European Journal of Pharmacology, 287, 215–217.PubMedCrossRefGoogle Scholar
  56. Reale, M., Iarlori, C., Thomas, A., Gambi, D., Perfetti, B., Di Nicola, M., & Onofrj, M. (2009). Peripheral cytokines profile in Parkinson’s disease. Brain, Behavior, and Immunity, 23, 55–63.PubMedCrossRefGoogle Scholar
  57. Robbins, T. W., & Roberts, A. C. (2007). Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cerebral Cortex, 17, 151–160.CrossRefGoogle Scholar
  58. Ross, G. W., Abbott, R. D., Petrovitch, H., Morens, D. M., Grandinetti, A., Tung, K. H., Tanner, C. M., Masaki, K. H., Blanchette, P. L., Curb, J. D., Popper, J. S., & White, L. R. (2000). Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA : The Journal of the American Medical Association, 283, 2674–2679.CrossRefGoogle Scholar
  59. Sääksjärvi, K., Knekt, P., Rissanen, H., Laaksonen, M. A., Reunanen, A., & Männistö, S. (2008). Prospective study of coffee consumption and risk of Parkinson’s disease. European Journal of Clinical Nutrition, 62, 908–915.PubMedCrossRefGoogle Scholar
  60. Schapira, A. H. (2006). Etiology of Parkinson’s disease. Neurology, 66, S10–S23.PubMedCrossRefGoogle Scholar
  61. Schiffmann, S. N., & Vanderhaeghen, J. J. (1993). Adenosine A(2) receptors regulate the gene expression of striatopallidal and striatonigral neurons. Journal of Neuroscience, 13, 1080–1087.PubMedGoogle Scholar
  62. Schwarzschild, M. A., & Ascherio, A. (2004). Caffeine and Parkinson’s disease. In A. Nehlig (Ed.), Coffee, tea, chocolate and the brain (pp. 147–163). Boca Raton: CRC Press.Google Scholar
  63. Schwarzschild, M. A., Chen, J. F., Tennis, M., Messing, S., Kamp, C., Ascherio, A., Holloway, R. G., Marek, K., Tanner, C. M., McDermott, M., Lang, A. E., & The Parkinson Study Group. (2003a). Relating caffeine consumption to Parkinson’s disease progression and dyskinesias development. Movement Disorders, 18, 1082–1083.CrossRefGoogle Scholar
  64. Schwarzschild, M. A., Xu, K., Oztas, E., Petzer, J. P., Castagnoli, K., Castagnoli, N., Jr., & Chen, J. F. (2003b). Neuroprotection by caffeine and more specific A(2A) receptor antagonists in animal models of Parkinson’s disease. Neurology, 61, S55–S61.PubMedCrossRefGoogle Scholar
  65. Schwarzschild, M. A., Agnati, L., Fuxe, K., Chen, J. F., & Morelli, M. (2006). Targeting adenosine A(2A) receptors in Parkinson’s disease. Trends in Neurosciences, 29, 647–654.PubMedCrossRefGoogle Scholar
  66. Shindou, T., Richardson, P. J., Mori, A., Kase, H., & Ichimura, M. (2003). Adenosine modulates the striatal GABAergic inputs to the globus pallidus via adenosine A(2A) receptors in rats. Neuroscience Letters, 352, 167–170.PubMedCrossRefGoogle Scholar
  67. Simola, N., Fenu, S., Baraldi, P. G., Tabrizi, M. A., & Morelli, M. (2006). Involvement of globus pallidus in the antiparkinsonian effects of adenosine A(2A) receptor antagonists. Experimental Neurology, 202, 255–257.PubMedCrossRefGoogle Scholar
  68. Simon, D. K., Swearingen, C. J., Hauser, R. A., Trugman, J. M., Aminoff, M. J., Singer, C., Truong, D., Tilley, B. C., & Investigators, N. E. T.-D. (2008). Caffeine and progression of Parkinson disease. Clinical Neuropharmacology, 31, 189–196.PubMedCentralPubMedCrossRefGoogle Scholar
  69. Stone, T. W., Ceruti, S., & Abbracchio, M. P. (2009). Adenosine receptors and neurological disease: Neuroprotection and neurodegeneration. Handbook of Experimental Pharmacology, 193, 535–587.PubMedCrossRefGoogle Scholar
  70. Xu, K., Xu, Y., Brown-Jermyn, D., Chen, J. F., Ascherio, A., Dluzen, D. E., & Schwarzschild, M. A. (2006). Estrogen prevents neuroprotection by caffeine in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Journal of Neuroscience, 26, 535–541.PubMedCrossRefGoogle Scholar
  71. Xu, K., Xu, Y. H., Chen, J. F., & Schwarzschild, M. A. (2010). Neuroprotection by caffeine: Time course and role of its metabolites in the MPTP model of Parkinson’s disease. Neuroscience, 167, 475–481.PubMedCentralPubMedCrossRefGoogle Scholar
  72. Yu, L., Shen, H. Y., Coelho, J. E., Araújo, I. M., Huang, Q. Y., Day, Y. J., Rebola, N., Canas, P. M., Rapp, E. K., Ferrara, J., Taylor, D., Müller, C. E., Linden, J., Cunha, R. A., & Chen, J. F. (2008). Adenosine A(2A) receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Annals of Neurology, 63, 338–346.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nicola Simola
    • 1
  • Annalisa Pinna
    • 1
    • 2
  • Lucia Frau
    • 1
  • Micaela Morelli
    • 1
    • 2
  1. 1.Department of Biomedical SciencesUniversity of CagliariCagliariItaly
  2. 2.CNR Institute of NeuroscienceCagliariItaly

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