Opposite Modulation of Peripheral Inflammation and Neuroinflammation by Adenosine A2A Receptors

  • Rodrigo A. Cunha
  • Jiang-Fan Chen
  • Michail V. Sitkovsky

Adenosine is a homeostatic modulator in all cells, being produced from intracellular ATP as a consequence of increased workload or noxious stimuli. Extracellular adenosine can then afford tissue protection by a combination of effects operated by inhibitory A1 receptors, which refrain metabolism, and facilitatory A2A receptors, which cause vasodilatation and act as a potent “Off” signal of immune/inflammatory cells in the periphery. Adenosine also acts as a neuromodulator in the brain through A1 receptor-mediated inhibition of excitatory transmission. However, adenosine also aggravates brain damage in chronic neurodegenerative conditions by mechanisms that may involve an A2A receptor-mediated potentiation of neuroinflammation. We will now review the evidences suggesting that A2A receptor control neuroinflammation and discuss the possible mechanisms underlying the opposite modulation by A2A receptors of peripheral inflammation and neuroinflammation.


Nerve Growth Factor Adenosine Receptor Brain Damage Peripheral Inflammation Neuroinflammatory Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

11. References

  1. Aisen, P.S., Schafer, K.A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K.L., Farlow, M.R., Jin, S., Thomas, R.G. and Thal, L.J., Alzheimer’s Disease Cooperative Study, 2003, Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289: 2819.PubMedGoogle Scholar
  2. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., Finch, C.E., Frautschy, S., Griffin, W.S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I.R., McGeer, P.L., et al., 2000, Inflammation and Alzheimer's disease. Neurobiol. Aging 21: 383.PubMedGoogle Scholar
  3. Aloisi, F., Ambrosini, E., Columba-Cabezas, S., Magliozzi, R. and Serafini, B., 2001, Intracerebral regulation of immune responses. Ann. Med. 33: 510.PubMedGoogle Scholar
  4. Andersen, J.K., 2004, Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 10: S18.PubMedGoogle Scholar
  5. Angelov, D.N., Waibel, S., Guntinas-Lichius, O., Lenzen, M., Neiss, W.F., Tomov, T.L., Yoles, E., Kipnis, J., Schori, H., Reuter, A., Ludolph, A., and Schwartz, M., 2003, Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 100: 4790.PubMedGoogle Scholar
  6. Angulo, E., Casadó, V., Mallol, J., Canela, E.I., Vinals, F., Ferrer, I., Lluis, C. and Franco, R., 2003, A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain Pathol. 13: 440.PubMedGoogle Scholar
  7. Apasov, S., Chen, J.F., Smith, P. and Sitkovsky, M., 2000, A2A receptor dependent and A2A receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency. Blood 95: 3859.PubMedGoogle Scholar
  8. Baldwin, S.A., Beal, P.R., Yao, S.Y., King, A.E., Cass, C.E. and Young, J.D., 2004, The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 447: 735.Google Scholar
  9. Barouch, R. and Schwartz, M., 2002, Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: implications for protective autoimmunity. FASEB J. 16: 1304.PubMedGoogle Scholar
  10. Batchelor, P.E., Liberatore, G.T., Wong, J.Y., Porritt, M.J., Frerichs, F., Donnan, G.A. and Howells, D.W., 1999, Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J. Neurosci. 19: 1708.PubMedGoogle Scholar
  11. Beal, M.F., 2003, Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann. N.Y. Acad. Sci. 991: 120.PubMedGoogle Scholar
  12. Bechmann, I., 2003, Failed central nervous system regeneration: a downside of immune privilege? Neuromolecular Med. 7: 217.Google Scholar
  13. Benner, E.J., Mosley, R.L., Destache, C.J., Lewis, T.B., Jackson-Lewis, V., Gorantla, S., Nemachek, C., Green, S.R., Przedborski, S. and Gendelman, H.E., 2004, Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc. Natl Acad. Sci. USA 101: 9435.PubMedGoogle Scholar
  14. Block, M.L. and Hong, J.S., 2005, Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76: 77.PubMedGoogle Scholar
  15. Boireau, A., Bordier, F., Dubedat, P., Peny, C. and Imperato, A., 1997, Thalidomide reduces MPTP-induced decrease in striatal dopamine levels in mice. Neurosci. Lett. 234: 123.PubMedGoogle Scholar
  16. Bouma, M.G., Jeunhomme, T.M., Boyle, D.L., Dentener, M.A., Voitenok, N.N., van den Wildenberg, F.A. and Buurman, W.A., 1997, Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors. J. Immunol. 158: 5400.PubMedGoogle Scholar
  17. Brambilla, R., Cottini, L., Fumagalli, M., Ceruti, S. and Abbracchio, M.P., 2003, Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia 43: 190.PubMedGoogle Scholar
  18. Brodie, C., Blumberg, P.M. and Jacobson, K.A., 1998, Activation of the A2A adenosine receptor inhibits nitric oxide production in glial cells. FEBS Lett. 429: 139.PubMedGoogle Scholar
  19. Bshesh, K., Zhao, B., Spight, D., Biaggioni, I., Feokistov, I., Denenberg, A., Wong, H.R. and Shanley, T.P., 2002, The A2A receptor mediates an endogenous regulatory pathway of cytokine expression in THP-1 cells. J. Leukoc. Biol. 72: 1027.PubMedGoogle Scholar
  20. Cardona, A.E., Pioro, E.P., Sasse, M.E., Kostenko, V., Cardona, S.M., Dijkstra, I.M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., Lee, J.C., Cook, D.N., Jung, S., Lira, S.A., Littman, D.R. and Ransohoff, R.M., 2006, Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9: 917.PubMedGoogle Scholar
  21. Carson, M.J. and Sutcliffe, J.G., 1999, Balancing function vs. self defense: the CNS as an active regulator of immune responses. J. Neurosci. Res. 55: 1.PubMedGoogle Scholar
  22. Cassada, D.C., Tribble, C.G., Laubach, V.E., Nguyen, B.N., Rieger, J.M., Linden, J., Kaza, A.K., Long, S.M., Kron, I.L. and Kern, J.A., 2001, An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion. J. Vasc. Surg. 34: 482.PubMedGoogle Scholar
  23. Cassada, D.C., Tribble, C.G., Long, S.M., Laubach, V.E., Kaza, A.K., Linden, J., Nguyen, B.N., Rieger, J.M., Fiser, S.M., Kron, I.L. and Kern, J.A., 2002, Adenosine A2A analogue ATL-146e reduces systemic tumor necrosing factor-alpha and spinal cord capillary platelet-endothelial cell adhesion molecule-1 expression after spinal cord ischemia. J. Vasc. Surg. 35: 994.PubMedGoogle Scholar
  24. Castren, E., 2004, Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection. Mol. Neurobiol. 29: 289.PubMedGoogle Scholar
  25. Chen, J.F., Xu, K., Petzer, J.P., Staal, R., Xu, Y.H., Beilstein, M., Sonsalla, P.K., Castagnoli, K., Castagnoli, N. Jr. and Schwarzschild, M.A., 2001, Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 21: RC143.Google Scholar
  26. Chen, H., Zhang, S.M., Hernan, M.A., Schwarzschild, M.A., Willett, W.C., Colditz, G.A., Speizer, F.E. and Ascherio, A., 2003, Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch. Neurol. 60: 1059.PubMedGoogle Scholar
  27. Ciruela, F., Casadó, V., Rodrigues, R.J., Lujan, R., Burgueño, J., Canals, M., Borycz, J., Rebola, N., Goldberg, S.R., Mallol, J., Cortes, A., Canela, E.I., Lopez-Gimenez, J.F., Milligan, G., Lluis, C., Cunha, R.A., Ferré, S. and Franco, R., 2006, Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J. Neurosci. 26: 2080.PubMedGoogle Scholar
  28. Coelho, J.E., de Mendonça, A. and Ribeiro, J.A., 2000, Presynaptic inhibitory receptors mediate the depression of synaptic transmission upon hypoxia in rat hippocampal slices. Brain Res. 869: 158.PubMedGoogle Scholar
  29. Coelho, J.E., Rebola, N., Fragata, I., Ribeiro, J.A., de Mendonça, A. and Cunha, R.A., 2006, Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus. Neuroscience 138: 1195.PubMedGoogle Scholar
  30. Cohen, S.B., Gill, S.S., Baer, G.S., Leo, B.M., Scheld, W.M. and Diduch, D.R., 2004, Reducing joint destruction due to septic arthrosis using an adenosine 2A receptor agonist. J. Orthop. Res. 22: 427.PubMedGoogle Scholar
  31. Cunha, R.A., 2001, Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem. Int. 38: 107.PubMedGoogle Scholar
  32. Cunha, R.A., 2005, Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Signal 1: 111.PubMedGoogle Scholar
  33. Cunha, R.A., Correia-de-Sá, P., Sebastião, A.M. and Ribeiro, J.A., 1996a, Preferential activation of excitatory adenosine receptors at rat hippocampal and neuromuscular synapses by adenosine formed from released adenine nucleotides. Br. J. Pharmacol. 119: 253.PubMedGoogle Scholar
  34. Cunha, R.A., Vizi, E.S., Ribeiro, J.A. and Sebastião, A.M., 1996b, Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high- but not low-frequency stimulation of rat hippocampal slices. J. Neurochem. 67: 2180.PubMedCrossRefGoogle Scholar
  35. Cunha, G.M.A., Canas, P.M., Oliveira, C.R. and Cunha, R.A., 2006, Increased density and synapto-protective effect of adenosine A2A receptors upon sub-chronic restraint stress. Neuroscience 141: 1775.PubMedGoogle Scholar
  36. Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L. and Gan, W.B., 2005, ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8: 752.PubMedGoogle Scholar
  37. Day, Y.J., Huang, L., McDuffie, M.J., Rosin, D.L., Ye, H., Chen, J.F., Schwarzschild, M.A., Fink, J.S., inden, J. and Okusa, M.D., 2003, Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J. Clin. Invest. 112: 883.PubMedGoogle Scholar
  38. Day, Y.J., Marshall, M.A., Huang, L., McDuffie, M.J., Okusa, M.D. and Linden, J., 2004, Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. Am. J. Physiol. 286: G285.Google Scholar
  39. Day, Y.L., Huang, L., Ye, N., Li, L., Linden, J. and Okusa, M.D., 2006, Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and INF-γ. J. Immunol. 176: 3108.PubMedGoogle Scholar
  40. de Mendonça, A. and Ribeiro, J.A., 1997, Adenosine and neuronal plasticity. Life Sci. 60: 245. de Mendonça, A., Sebastião, A.M. and Ribeiro, J.A., 2000, Adenosine: does it have a neuroprotective role after all? Brain Res. Rev. 33: 258.Google Scholar
  41. de Simone, R., Ajmone-Cat, M.A. and Minghetti, L., 2004, Atipical anti-inflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol. Neurobiol. 29: 197.PubMedGoogle Scholar
  42. Dixon, A.K., Widdowson, L. and Richardson, P.J., 1997, Desensitisation of the adenosine A1 receptor by the A2A receptor in the rat striatum. J. Neurochem. 69: 315.PubMedCrossRefGoogle Scholar
  43. Dodart, J.C., Bales, K.R., Gannon, K.S., Greene, S.J., DeMattos, R.B., Mathis, C., DeLong, C.A., Wu, S., Wu, X., Holtzman, D.M. and Paul, S.M., 2002, Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat. Neurosci. 5: 452.PubMedGoogle Scholar
  44. Dong, Y. and Benveniste, E.N., 2001, Immune function of astrocytes. Glia 36: 180.PubMedGoogle Scholar
  45. Duarte, J.M., Oliveira, C.R., Ambrósio, A.F. and Cunha, R.A., 2006, Modification of adenosine A1 and A2A receptor density in the hippocampus of streptozotocin-induced diabetic rats. Neurochem. Int. 48: 144.PubMedGoogle Scholar
  46. Dunwiddie, T.V., 1999, Adenosine and suppression of seizures. Adv. Neurol. 79: 1001.PubMedGoogle Scholar
  47. Dunwiddie, T.V. and Masino, S.A., 2001 The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci. 24: 31.PubMedGoogle Scholar
  48. Ekdahl, C.T., Claasen, J.H., Bonde, S., Kokaia, Z. and Lindvall, O., 2003, Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 100: 13632.PubMedGoogle Scholar
  49. Elkabes, S., DiCicco-Bloom, E.M. and Black, I.B., 1996, Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16: 2508.PubMedGoogle Scholar
  50. Elward, K. and Gasque, P., 2003, “Eat me” and “don’t eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system. Mol. Immunol. 40: 85.Google Scholar
  51. Farber, K. and Kettenmann, H., 2005, Physiology of microglial cells. Brain Res. Rev. 48: 133.PubMedGoogle Scholar
  52. Faulkner, J.R., Herrmann, J.E., Woo, M.J., Tansey, K.E., Doan, N.B. and Sofroniew, M.V., 2004, Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24: 2143.PubMedGoogle Scholar
  53. Fedele, D.E., Li, T., Lan, J.Q., Fredholm, B.B. and Boison, D., 2006 Adenosine A1 receptors are crucial in keeping an epileptic focus localized. Exp. Neurol. 200: 184.PubMedGoogle Scholar
  54. Fellin, T. and Carmignoto, G., 2004, Neurone-to-astrocyte signaling in the brain represents a distinct multifunctional unit. J. Physiol. 559: 3.PubMedGoogle Scholar
  55. Ferré, S., Borycz, J., Goldberg, S.R., Hope, B.T., Morales, M., Lluis, C., Franco, R., Ciruela, F. and Cunha, R.A., 2005, Role of adenosine in the control of homosynaptic plasticity in striatal excitatory synapses. J. Integr. Neurosci. 4: 445.PubMedGoogle Scholar
  56. Fiebich, B.L., Biber, K., Lieb, K., van Calker, D., Berger, M., Bauer, J. and Gebicke-Haerter, P.J., 1996, Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. Glia 18: 152.PubMedGoogle Scholar
  57. Flugel, A., Matsumuro, K., Neumann, H., Klinkert, W.E., Birnbacher, R., Lassmann, H., Otten, U. and Wekerle, H., 2001, Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur. J. Immunol. 31: 11.PubMedGoogle Scholar
  58. Fredholm, B.B., 1997, Adenosine and neuroprotection. Int. Rev. Neurobiol. 40: 259.PubMedGoogle Scholar
  59. Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Klotz, K.N. and Linden, J., 2001, International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53: 527.PubMedGoogle Scholar
  60. Fredholm, B.B., Cunha, R.A. and Svenningsson, P., 2003, Pharmacology of adenosine A2A receptors and therapeutic applications. Curr. Top. Med. Chem. 3: 413.PubMedGoogle Scholar
  61. Fredholm, B.B., Chen, J.F., Cunha, R.A., Svenningsson, P. and Vaugeois, J.M., 2005, Adenosine and brain function. Int. Rev. Neurobiol. 63: 191.PubMedGoogle Scholar
  62. Gandy, S. and Heppner, F.L., 2005, Alzheimer’s amyloid immunotherapy: quo vadis? Lancet Neurol. 4: 452.PubMedGoogle Scholar
  63. Gao, H.M., Liu, B., Zhang, W. and Hong, J.S., 2003, Novel anti-inflammatory therapy for Parkinson’s disease. Trends Pharmacol. Sci. 24: 395.PubMedGoogle Scholar
  64. Gasque, P., Dean, Y.D., McGreal, E.P., VanBeek, J. and Morgan, B.P., 2000, Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49: 171.PubMedGoogle Scholar
  65. Gebicke-Haerter, P.J., 2001, Microglia in neurodegeneration: molecular aspects. Microsc. Res. Tech. 54: 47.PubMedGoogle Scholar
  66. Gebicke-Haerter, P.J., Christoffel, F., Timmer, J., Northoff, H., Berger, M. and Van Calker, D., 1996, Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation. Neurochem. Int. 29: 37.PubMedGoogle Scholar
  67. Gerevich, Z., Wirkner, K. and Illes, P., 2002, Adenosine A2A receptors inhibit the N-methyl-D-aspartate component of excitatory synaptic currents in rat striatal neurons. Eur. J. Pharmacol. 451: 161.PubMedGoogle Scholar
  68. Giovannoni, G. and Baker, D., 2003, Inflammatory disorders of the central nervous system. Curr. Opin. Neurol. 16: 347.PubMedGoogle Scholar
  69. Giraudon, P., Vincent, P. and Vuaillat, C., 2005, T-cells in neuronal injury and repair: semaphorins and related T-cell signals. Neuromol. Med. 7: 207.Google Scholar
  70. Greene, R.W. and Haas, H.L., 1991, The electrophysiology of adenosine in the mammalian central nervous system. Prog. Neurobiol. 36: 329.PubMedGoogle Scholar
  71. Hammarberg, H., Lidman, O., Lundberg, C., Eltayeb, S.Y., Gielen, A.W., Muhallab, S., Svenningsson, A., Linda, H., van Der Meide, P.H., Cullheim, S., Olsson, T. and Piehl, F., 2000, Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J. Neurosci. 20: 5283.PubMedGoogle Scholar
  72. Hanisch, U.K., 2002, Microglia as a source and target of cytokines. Glia 40: 140.PubMedGoogle Scholar
  73. Harada, N., Okajima, K., Murakami, K., Usune, S., Sato, C., Ohshima, K. and Katsuragi, T., 2000, Adenosine and selective A2A receptor agonists reduce ischemia/reperfusion injury of rat liver mainly by inhibiting leukocyte activation. J. Pharmacol. Exp. Ther. 294: 1034.PubMedGoogle Scholar
  74. Harrison, J.K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R.K., Streit, W.J., Salafranca, M.N., Adhikari, S., Thompson, D.A., Botti, P., Bacon, K.B. and Feng, L., 1998, Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95: 10896.PubMedGoogle Scholar
  75. Hartmann, A., Hunot, S. and Hirsch, E.C., 2003, Inflammation and dopaminergic neuronal loss in Parkinson’s disease: a complex matter. Exp. Neurol. 184: 561.PubMedGoogle Scholar
  76. Hasko, G. and Cronstein, B.N., 2004. Adenosine: an endogenous regulator of innate immunity. Trends Immunol. 25: 33.PubMedGoogle Scholar
  77. Hasko, G., Kuhel, D.G., Chen, J.F., Schwarzschild, M.A., Deitch, E.A., Mabley, J.G., Marton, A. and Szabo, C., 2000, Adenosine inhibits IL-12 and TNF-α production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J. 14: 2065.PubMedGoogle Scholar
  78. Hasko, G., Pacher, P., Vizi, E.S. and Illes, P., 2005, Adenosine receptor signaling in the brain immune system. Trends Pharmacol. Sci. 26: 511.PubMedGoogle Scholar
  79. Hauwel, M., Furon, E., Canova, C., Griffiths, M., Neal, J. and Gasque, P., 2005, Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, “protective” glial stem cells and stromal ependymal cells. Brain Res. Rev. 48: 220.PubMedGoogle Scholar
  80. Heese, K., Fiebich, B.L., Bauer, J. and Otten, U., 1997, Nerve growth factor (NGF) expression in rat microglia is induced by adenosine A2a-receptors. Neurosci. Lett. 231: 83.PubMedGoogle Scholar
  81. Heese, K., Hock, C. and Otten, U., 1998, Inflammatory signals induce neurotrophin expression in human microglial cells. J. Neurochem. 70: 699.PubMedCrossRefGoogle Scholar
  82. Herrera, A.J., Tomas-Camardiel, M., Venero, J.L., Cano, J. and Machado, A., 2005, Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons. J. Neural Transm. 112: 111.PubMedGoogle Scholar
  83. Herx, L.M., Rivest, S. and Yong, V.W., 2000, Central nervous system-initiated inflammation and neurotrophism in trauma: IL-1β is required for the production of ciliary neurotrophic factor. J. Immunol. 165: 2232.PubMedGoogle Scholar
  84. Hickey, W.F., Hsu, B.L. and Kimura, H., 1991, T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28: 254.PubMedGoogle Scholar
  85. Hindley, S., Herman, M.A. and Rathbone, M.P., 1994, Stimulation of reactive astrogliosis in vivo by extracellular adenosine diphosphate or an adenosine A2 receptor agonist. J. Neurosci. Res. 38: 399.PubMedGoogle Scholar
  86. Hirsch, E.C., Breidert, T., Rousselet, E., Hunot, S., Hartmann, A. and Michel, P.P., 2003, The role of glial reaction and inflammation in Parkinson’s disease. Ann. N.Y. Acad. Sci. 991: 214.PubMedCrossRefGoogle Scholar
  87. Hirschberg, D.L., Moalem, G., He, J., Mor, F., Cohen, I.R. and Schwartz, M., 1998, Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma. J. Neuroimmunol. 89: 88.PubMedGoogle Scholar
  88. Huang, S., Apasov, S., Koshiba, M. and Sitkovsky, M., 1997, Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90: 1600.PubMedGoogle Scholar
  89. Inoue, K., 2006, The function of microglia through purinergic receptors: Neuropathic pain and cytokine release. Pharmacol. Ther. 109: 210.PubMedGoogle Scholar
  90. int’ Veld, B.A., Ruitenberg, A., Hofman, A., Launer, L.J., van Duijn, C.M., Stijnen, T., Breteler, M.M. and Stricker, B.H., 2001, Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345: 1515.Google Scholar
  91. Irani, D.N., Lin, K.I. and Griffin, D.E., 1997, Regulation of brain-derived T cells during acute central nervous system inflammation. J. Immunol. 158: 2318.PubMedGoogle Scholar
  92. Jensen, M.B., Finsen, B. and Zimmer, J., 1997, Morphological and immunophenotypic microglial changes in denervated fascia dentate of adult rats: correlation with blood-brain barrier damage and astroglial reactions. Exp. Neurol. 143: 103.PubMedGoogle Scholar
  93. Jones, T.B., Basso, D.M., Sodhi, A., Pan, J.Z., Hart, R.P., MacCallum, R.C., Lee, S., Whitacre, C.C. and Popovich, P.G., 2002, Pathological CNS autoimmune disease triggered by traumatic spinal cord injury: implications for autoimmune vaccine therapy. J. Neurosci. 22: 2690.PubMedGoogle Scholar
  94. Kerschensteiner, M., Stadelmann, C., Dechant, G., Wekerle, H. and Hohlfeld, R., 2003 Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann. Neurol. 53: 292.PubMedGoogle Scholar
  95. Khimenko, P.L., Moore, T.M., Hill, L.W., Wilson, P.S., Coleman, S., Rizzo, A. and Taylor, A.E., 1995, Adenosine A2 receptors reverse ischemia-reperfusion lung injury independent of beta-receptors. J. Appl. Physiol. 78: 990.PubMedGoogle Scholar
  96. Kim, W.G., Mohney, R.P., Wilson, B., Jeohn, G.H., Liu, B. and Hong, J.S., 2000, Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity: role of microglia. J. Neurosci. 20: 6309.PubMedGoogle Scholar
  97. Kipnis, J., Mizrahi, T., Hauben, E., Shaked, I., Shevach, E. and Schwartz, M., 2002, Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc. Natl Acad. Sci. USA 99: 15620.PubMedGoogle Scholar
  98. Kloss, C.U., Bohatscheck, M., Kreutzberg, G.W. and Raivich, G., 2001, Effect of lipopolysaccharide on the morphology and integrin immunoreactivity of ramified microglia in mouse brain and in cell culture. Exp. Neurol. 168: 32.PubMedGoogle Scholar
  99. Kreutzberg, G.W., 1996, Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19: 312.PubMedGoogle Scholar
  100. Küst, B.M., Biber, K., van Calker, D. and Gebicke-Haerter, P.J., 1999, Regulation of K+ channel mRNA expression by stimulation of adenosine A2a-receptors in cultured rat microglia. Glia 25: 120.PubMedGoogle Scholar
  101. Ladeby, R., Wirenfeldt, M., Garcia-Ovejero, D., Fenger, C., Dissing-Olesen, L., Dalmau, I. and Finsen, B., 2005, Microglial cell population dynamics in the injured adult central nervous system. Brain Res. Rev. 48: 196.PubMedGoogle Scholar
  102. Lappas, C.M., Rieger, J.M. and Linden, J., 2005, A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells. J. Immunol. 174: 1073.PubMedGoogle Scholar
  103. Lee, K.S., Tetzlaff, W. and Kreutzberg, G.W., 1986, Rapid down regulation of hippocampal adenosine receptors following brief anoxia. Brain Res. 380: 155.PubMedGoogle Scholar
  104. Lee, Y.C., Chien, C.L., Sun, C.N., Huang, C.L., Huang, N.K., Chiang, M.C., Lai, H.L., Lin, Y.S., Chou, S.Y., Wang, C.K., Tai, M.H., Liao, W.L., Lin, T.N., Liu, F.C. and Chern, Y., 2003, Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur. J. Neurosci. 18: 1786.PubMedGoogle Scholar
  105. Lee, H.K., Choi, S.S., Han, K.J., Han, E.J. and Suh, H.W., 2004, Roles of adenosine receptors in the regulation of kainic acid-induced neurotoxic responses in mice. Mol. Brain Res. 125: 76.PubMedGoogle Scholar
  106. Leibovich, S.J., Chen, J.F., Pinhal-Enfield, G., Belem, P.C., Elson, G., Rosania, A., Ramanathan, M., Montesinos, C., Jacobson, M., Schwarzschild, M.A., Fink, J.S. and Cronstein, B., 2002, Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A2A receptor agonists and endotoxin. Am. J. Pathol. 160: 2231.PubMedGoogle Scholar
  107. Linden, J., 2005, Adenosine in tissue protection and tissue regeneration. Mol. Pharmacol. 67: 1385.PubMedGoogle Scholar
  108. Link, A.A., Kino, T., Worth, J.A., McGuire, J.L., Crane, M.L., Chrousos, G.P., Wilder, R.L. and Elenkov, I.J., 2000, Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J. Immunol. 164: 436.PubMedGoogle Scholar
  109. Lipton, S.A. and Rosenberg, P.A., 1994, Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330: 613.PubMedGoogle Scholar
  110. Liu, B. and Hong, J.S., 2003, Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304: 1.PubMedGoogle Scholar
  111. Lopes, L.V., Cunha, R.A. and Ribeiro, J.A., 1999, Cross talk between A1 and A2A adenosine receptors in the hippocampus and cortex of young adult and old rats. J. Neurophysiol. 82: 3196.PubMedGoogle Scholar
  112. Lopes, L.V., Cunha, R.A., Kull, B., Fredholm, B.B. and Ribeiro, J.A., 2002, Adenosine A2A receptor facilitation of hippocampal synaptic transmission is dependent on tonic A1 receptor inhibition. Neuroscience 112: 319.PubMedGoogle Scholar
  113. Lopes, L.V., Halldner, L., Rebola, N., Johansson, B., Ledent, C., Chen, J.F., Fredholm, B.B. and Cunha, R.A., 2004, Binding of the prototypical adenosine A2A receptor agonist CGS 21680 to the cerebral cortex of adenosine A1 and A2A receptor knockout mice. Br. J. Pharmacol. 141: 1006.PubMedGoogle Scholar
  114. Lucas, S.M., Rothwell, N.J. and Gibson, R.M., 2006, The role of inflammation in CNS injury and disease. Br.J. Pharmacol. 147: S232.PubMedGoogle Scholar
  115. Lucchi, R., Latini, S., de Mendonça, A., Sebastião, A.M. and Ribeiro, J.A., 1996, Adenosine by activating A1 receptors prevents GABAA-mediated actions during hypoxia in the rat hippocampus. Brain Res. 732: 261.PubMedGoogle Scholar
  116. Lyons, S.A., Pastor, A., Ohlemeyer, C., Kann, O., Wiegand, F., Prass, K., Kettenmann, H. and Dirnagl, U., 2000, Distinct physiologic properties of microglia and blood-borne cells in rat brain slices after permanent middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 20: 1537.PubMedGoogle Scholar
  117. Maddock, H.L., Broadley, K.J., Bril, A. and Khandoudi, N., 2001, Role of endothelium in ischaemia-induced myocardial dysfunction of isolated working hearts: cardioprotection by activation of adenosine A2A receptors. J. Auton. Pharmacol. 21: 263.PubMedGoogle Scholar
  118. Magnus, T., Chan, A., Linker, R.A., Toyka, K.V. and Gold, R., 2002, Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: implications for the role of glial cells in the inflamed central nervous system. J. Neuropathol. Exp. Neurol. 61: 760.PubMedGoogle Scholar
  119. Marchetti, B. and Abbracchio, M.P., 2005, To be or not to be (inflamed)-is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol. Sci. 26: 517.PubMedGoogle Scholar
  120. Marchi, M., Raiteri, L., Risso, F., Vallarino, A., Bonfanti, A., Monopoli, A., Ongini, E. and Raiteri, M., 2002, Effects of adenosine A1 and A2A receptor activation on the evoked release of glutamate from rat cerebrocortical synaptosomes. Br. J. Pharmacol. 136: 434.PubMedGoogle Scholar
  121. Marcoli, M., Raiteri, L., Bonfanti, A., Monopoli, A., Ongini, E., Raiteri, M. and Maura, G., 2003, Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. Neuropharmacology 45: 201.PubMedGoogle Scholar
  122. Marcoli, M., Bonfanti, A., Roccatagliata, P., Chiaramonte, G., Ongini, E., Raiteri, M. and Maura, G., 2004, Glutamate efflux from human cerebrocortical slices during ischemia: vesicular-like mode of glutamate release and sensitivity to A2A adenosine receptor blockade. Neuropharmacology 47: 884.PubMedGoogle Scholar
  123. Matsuura, K., Kabuto, H., Makino, H. and Ogawa, N., 1997, Initial cyclosporin A but not glucocorticoid treatment promotes recovery of striatal dopamine concentration in 6-hydroxydopamine lesioned mice. Neurosci. Lett. 230: 191.PubMedGoogle Scholar
  124. Matyszak, M.K., 1998, Inflammation in the CNS: balance between immunological privilege and immune responses. Prog. Neurobiol. 56: 19.PubMedGoogle Scholar
  125. Mayne, M., Fotheringham, J., Yan, H.J., Power, C., Del Bigio, M.R., Peeling, J. and Geiger, J.D., 2001, Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage. Ann. Neurol. 49: 727.PubMedGoogle Scholar
  126. McColl, S.R., St-Onge, M., Dussault, A.A., Laflamme, C., Bouchard, L., Boulanger, J. and Pouliot, M., 2006, Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils. FASEB J. 20: 187.PubMedGoogle Scholar
  127. McGeer, P.L. and McGeer, E.G., 2002, Local neuroinflammation and the progression of Alzheimer’s disease. J. Neurovirol. 8: 529.PubMedGoogle Scholar
  128. McGeer, P.L. and McGeer, E.G., 2004, Inflammation and neurodegeneration in Parkinson's disease. Parkinsonism Relat. Disord. 10: S3.PubMedGoogle Scholar
  129. McGeer, P.L. and McGeer, E.G., 2006, NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol. Aging. 28: 639.PubMedGoogle Scholar
  130. McGeer, E.G., Klegeris, A. and McGeer, P.L., 2005, Inflammation, the complement system and the diseases of aging. Neurobiol. Aging 26(Suppl 1): 94.PubMedGoogle Scholar
  131. McPherson, J.A., Barringhaus, K.G., Bishop, G.G., Sanders, J.M., Rieger, J.M., Hesselbacher, S.E., Gimple, L.W., Powers, E.R., Macdonald, T., Sullivan, G., Linden, J. and Sarembock, I.J., 2001, Adenosine A2A receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model. Arterioscler. Thromb. Vasc. Biol. 21: 791.PubMedGoogle Scholar
  132. Melchior, B., Puntambekar, S.S. and Carson, M.J., 2006, Microglia and the control of autoreactive T cell responses. Neurochem. Int. 49: 145.PubMedGoogle Scholar
  133. Minghetti, L., 2005, Role of inflammation in neurodegenerative diseases. Curr. Opin. Neurol. 18: 315.PubMedGoogle Scholar
  134. Miwa, T., Furukawa, S., Nakajima, K., Furukawa, Y. and Kohsaka, S., 1997, Lipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia. J. Neurosci. Res. 50: 1023.PubMedGoogle Scholar
  135. Mizuma, H., Takagi, K., Miyake, K., Takagi, N., Ishida, K., Takeo, S., Nitta, A., Nomoto, H., Furukawa, Y. and Furukawa, S. 1999, Microsphere embolism-induced elevation of nerve growth factor level and appearance of nerve growth factor immunoreactivity in activated T-lymphocytes in the rat brain. J. Neurosci. Res. 55: 749.PubMedGoogle Scholar
  136. Moalem, G., Leibowitz-Amit, R., Yoles, E., Mor, F., Cohen, I.R. and Schwartz, M., 1999, Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5: 49.PubMedGoogle Scholar
  137. Moalem, G., Gdalyahu, A., Shani, Y., Otten, U., Lazarovici, P., Cohen, I.R. and Schwartz, M., 2000, Production of neurotrophins by activated T cells: implications for neuroprotective autoimmunity. J. Autoimmun. 15: 331.PubMedGoogle Scholar
  138. Modlinger, P.S. and Welch, W.J., 2003, Adenosine A1 receptor antagonists and the kidney. Curr. Opin. Nephrol. Hypertens. 12: 497.PubMedGoogle Scholar
  139. Monje, M.L., Toda, H. and Palmer, T.D., 2003, Inflammatory blockade restores adult hippocampal neurogenesis. Science 302: 1760.PubMedGoogle Scholar
  140. Montesinos, M.C., Desai, A., Chen, J.F., Yee, H., Schwarzschild, M.A., Fink, J.S. and Cronstein, B.N., 2002, Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. Am. J. Pathol. 160: 2009.PubMedGoogle Scholar
  141. Morale, M.C., Serra, P.A., L’episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Gennuso, F., Giaquinta, G., Rocchitta, G., Desole, M.S., Miele, E. and Marchetti, B., 2006, Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience 138: 869.PubMedGoogle Scholar
  142. Nash, J.E. and Brotchie, J.M., 2000, A common signaling pathway for striatal NMDA and adenosine A2a receptors: implications for the treatment of Parkinson's disease. J. Neurosci. 20: 7782.PubMedGoogle Scholar
  143. Nataf, S., Anginot, A., Vuaillat, C., Malaval, L., Fodil, N., Chereul, E., Langlois, J.B., Dumontel, C., Cavillon, G., Confavreux, C., Mazzorana, M., Vico, L., Belin, M.F., Vivier, E., Tomasello, E. and Jurdic, P., 2005, Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am. J. Pathol. 166: 275.PubMedGoogle Scholar
  144. Neuhaus, O., Farina, C., Wekerle, H. and Hohlfeld, R., 2001, Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56: 702.PubMedGoogle Scholar
  145. Neumann, H., Misgeld, T., Matsumuro, K. and Wekerle, H., 1998, Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc. Natl Acad. Sci. USA 95: 5779.PubMedGoogle Scholar
  146. Newby, A.C., 1984, Adenosine and the concept of retaliatory metabolite. Trends Biochem. Sci. 9: 42.Google Scholar
  147. Nguyen, M.D., Julien, J.P. and Rivest, S., 2002, Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat. Rev. Neurosci. 3: 216.PubMedGoogle Scholar
  148. Niederkorn, J.Y., 2006, See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat. Immunol. 7: 354.PubMedGoogle Scholar
  149. Nimmerjahn, A., Kirchhoff, F. and Helmchen, F., 2005, Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314.PubMedGoogle Scholar
  150. Nishizaki, T., Nagai, K., Nomura, T., Tada, H., Kanno, T., Tozaki, H., Li, X.X., Kondoh, T., Kodama, N., Takahashi, E., Sakai, N., Tanaka, K. and Saito, N., 2002, A new neuromodulatory pathway with a glial contribution mediated via A2a adenosine receptors. Glia 39: 133.PubMedGoogle Scholar
  151. Odashima, M., Otaka, M., Jin, M., Komatsu, K., Wada, I., Matsuhashi, T., Horikawa, Y., Hatakeyama, N., Oyake, J., Ohba, R., Linden, J. and Watanabe, S., 2005a, Selective adenosine A2A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats. J. Gastroenterol. Hepatol. 20: 275.PubMedGoogle Scholar
  152. Odashima, M., Otaka, M., Jin, M., Komatsu, K., Wada, I., Matsuhashi, T., Horikawa, Y., Hatakeyama, N., Oyake, J., Ohba, R., Linden, J. and Watanabe, S., 2005b, Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice. J. Gastroenterol. 40: 526.PubMedGoogle Scholar
  153. Odashima, M., Bamias, G., Rivera-Nieves, J., Linden, J., Nast, C.C., Moskaluk, C.A., Marini, M., Sugawara, K., Kozaiwa, K., Otaka, M., Watanabe, S. and Cominelli, F., 2005c, Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129: 26.PubMedGoogle Scholar
  154. Ogata, T., Nakamura, Y. and Schubert, P., 1996, Potentiated cAMP rise in metabotropically stimulated rat cultured astrocytes by a Ca2+-related A1/A2 adenosine receptor cooperation. Eur. J. Neurosci. 8: 1124.PubMedGoogle Scholar
  155. Ohta, A. and Sitkovsky, M., 2001, Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414: 916.PubMedGoogle Scholar
  156. O’Keefe, G.M., Nguyen, V.T. and Benveniste, E.N., 2002, Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases. J. Neurovirol. 8: 496.PubMedGoogle Scholar
  157. Okusa, M.D., Linden, J., Huang, L., Rieger, J.M., Macdonald, T.L. and Huynh, L.P., 2000, A2A adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion. Am. J. Physiol. 279: F809.Google Scholar
  158. Olsson, T., Cronberg, T., Rytter, A., Asztely, F., Fredholm, B.B., Smith, M.L. and Wieloch, T., 2004, Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro. Eur. J. Neurosci. 20: 1197.PubMedGoogle Scholar
  159. O’Regan, M., 2005, Adenosine and the regulation of cerebral blood flow. Neurol. Res. 27: 175.PubMedGoogle Scholar
  160. Osswald, H., Vallon, V. and Muhlbauer, B., 1996, Role of adenosine in tubuloglomerular feedback and acute renal failure. J. Auton. Pharmacol. 16: 377.PubMedGoogle Scholar
  161. Panther, E., Idzko, M., Herouy, Y., Rheinen, H., Gebicke-Haerter, P.J., Mrowietz, U., Dichmann, S. and Norgauer, J., 2001, Expression and function of adenosine receptors in human dendritic cells. FASEB J. 15: 1963.PubMedGoogle Scholar
  162. Panther, E., Corinti, S., Idzko, M., Herouy, Y., Napp, M., la Sala, A., Girolomoni, G. and Norgauer, J., 2003, Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101: 3985.PubMedGoogle Scholar
  163. Pearson, T. and Frenguelli, B.G., 2004, Adrenoceptor subtype-specific acceleration of the hypoxic depression of excitatory synaptic transmission in area CA1 of the rat hippocampus. Eur. J. Neurosci. 20: 1555.PubMedGoogle Scholar
  164. Peirce, S.M., Skalak, T.C., Rieger, J.M., Macdonald, T.L. and Linden, J., 2001, Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am. J. Physiol. 281: H67.Google Scholar
  165. Pellerin, L., 2005 How astrocytes feed hungry neurons. Mol. Neurobiol. 32: 59.PubMedGoogle Scholar
  166. Perry, V.H., Andersson, P.B. and Gordon, S., 1933, Macrophages and inflammation in the central nervous system. Trends Neurosci. 16: 268.Google Scholar
  167. Piehl, F. and Lidman, O., 2001, Neuroinflammation in the rat-CNS cells and their role in the regulation of immune reactions. Immunol. Rev. 184: 212.PubMedGoogle Scholar
  168. Pinhal-Enfield, G., Ramanathan, M., Hasko, G., Vogel, S.N., Salzman, A.L., Boons, G.J. and Leibovich, S.J., 2003, An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A2A receptors. Am. J. Pathol. 163: 711.PubMedGoogle Scholar
  169. Pinto-Duarte, A., Coelho, J.E., Cunha, R.A., Ribeiro, J.A. and Sebastião, A.M., 2005, Adenosine A2A receptors control the extracellular levels of adenosine through modulation of nucleoside transporters activity in the rat hippocampus. J. Neurochem. 93: 595.PubMedGoogle Scholar
  170. Pintor, A., Galluzzo, M., Grieco, R., Pezzola, A., Reggio, R. and Popoli, P., 2004, Adenosine A2A receptor antagonists prevent the increase in striatal glutamate levels induced by glutamate uptake inhibitors. J. Neurochem. 89: 152.PubMedGoogle Scholar
  171. Platts, S.H., Linden, J. and Duling, B.R., 2003, Rapid modification of the glycocalyx caused by ischemia-reperfusion is inhibited by adenosine A2A receptor activation. Am. J. Physiol. 284: H2360.Google Scholar
  172. Polazzi, E., Gianni, T. and Contestabile, A., 2001, Microglial cells protect cerebellar granule neurons from apoptosis: evidence for reciprocal signaling. Glia 36: 271.PubMedGoogle Scholar
  173. Popoli, P., Frank, C., Tebano, M.T., Potenza, R.L., Pintor, A., Domenici, M.R., Nazzicone, V., Pezzola, A. and Reggio, R., 2003, Modulation of glutamate release and excitotoxicity by adenosine A2A receptors. Neurology 61: S69.PubMedGoogle Scholar
  174. Ponzio, T.A., Wang, Y.F. and Hatton, G.I., 2006, Activation of adenosine A2A receptors alters postsynaptic currents and depolarizes neurons of the supraoptic nucleus. Am. J. Physiol. 291: 359.Google Scholar
  175. Raivich, G., 2005, Like cops on the beat: the active role of resting microglia. Trends Neurosci. 28: 571.PubMedGoogle Scholar
  176. Raivich, G., Bohatschek, M., Kloss, C.U., Werner, A., Jones, L.L. and Kreutzberg, G.W., 1999, Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res. Rev. 30: 77.PubMedGoogle Scholar
  177. Randolph, D.A. and Fathman, C.G., 2006, Cd4+Cd25+ regulatory T cells and their therapeutic potential. Annu. Rev. Med. 57: 381.PubMedGoogle Scholar
  178. Ransohoff, R.M. and Tani, M., 1998, Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci. 21: 154.PubMedGoogle Scholar
  179. Rebola, N., Pinheiro, P.C., Oliveira, C.R., Malva, J.O. and Cunha, R.A., 2003, Subcellular localization of adenosine A1 receptors in nerve terminals and synapses of the rat hippocampus. Brain Res. 987: 49.PubMedGoogle Scholar
  180. Rebola, N., Canas, P.M., Oliveira, C.R. and Cunha, R.A., 2005a, Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132: 893.PubMedGoogle Scholar
  181. Rebola, N., Rodrigues, R.J., Lopes, L.V., Richardson, P.J., Oliveira, C.R. and Cunha, R.A., 2005b, Adenosine A1 and A2A receptors are co-expressed in pyramidal neurons and co-localized in glutamatergic nerve terminals of the rat hippocampus. Neuroscience 133: 79.PubMedGoogle Scholar
  182. Rebola, N., Porciúncula, L.O., Lopes, L.V., Oliveira, C.R., Soares-da-Silva, P. and Cunha, R.A., 2005c, Long-term effect of convulsive behavior on the density of adenosine A1 and A2A receptors in the rat cerebral cortex. Epilepsia 46(Suppl 5): 159.PubMedGoogle Scholar
  183. Ritchie, P.K., Spangelo, B.L., Krzymowski, D.K., Rossiter, T.B., Kurth, E. and Judd, A.M., 1997, Adenosine increases interleukin 6 release and decreases tumour necrosis factor release from rat adrenal zona glomerulosa cells, ovarian cells, anterior pituitary cells, and peritoneal macrophages. Cytokine 9: 187.PubMedGoogle Scholar
  184. Rodrigues, R.J., Alfaro, T.M., Rebola, N., Oliveira, C.R. and Cunha, R.A., 2005, Co-localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. J. Neurochem. 92: 433.PubMedGoogle Scholar
  185. Ross, S.D., Tribble, C.G., Linden, J., Gangemi, J.J., Lanpher, B.C., Wang, A.Y. and Kron, I.L., 1999, Selective adenosine-A2A activation reduces lung reperfusion injury following transplantation. J. Heart Lung Transplant. 18: 994.PubMedGoogle Scholar
  186. Rossi, D.J., Oshima, T. and Attwell, D., 2000, Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403: 316.PubMedGoogle Scholar
  187. Sargsyan, S.A., Monk, P.N. and Shaw, P.J., 2005, Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 51: 241.PubMedGoogle Scholar
  188. Saura, J., Angulo, E., Ejarque, A., Casadó, V., Tusell, J.M., Moratalla, R., Chen, J.F., Schwarzschild, M.A., Lluis, C., Franco, R. and Serratosa, J., 2005, Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia. J. Neurochem. 95: 919.PubMedGoogle Scholar
  189. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg, I., Motter, R., Mutter, L., Soriano, F., Shopp, G., Vasquez, N., Vandevert, C., Walker, S., Wogulis, M., Yednock, T., Games, D. and Seubert, P., 1999, Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173.PubMedGoogle Scholar
  190. Schnurr, M., Toy, T., Shin, A., Hartmann, G., Rothenfusser, S., Soellner, J., Davis, I.D., Cebon, J. and Maraskovsky, E., 2004, Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood 103: 1391.PubMedGoogle Scholar
  191. Schwartz, M. and Kipnis, J., 2005, Therapeutic T cell-based vaccination for neurodegenerative disorders: the role of CD4+CD25+ regulatory T cells. Ann. N.Y. Acad. Sci. 1051: 701.PubMedGoogle Scholar
  192. Schwartz, M. and Moalem, G., 2001, Beneficial immune activity after CNS injury: prospects for vaccination. J. Neuroimmunol. 113: 185.PubMedGoogle Scholar
  193. Schwartz, M., Moalem, G., Leibowitz-Amit, R. and Cohen, I.R., 1999, Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci. 22: 295.PubMedGoogle Scholar
  194. Schwartz, M., Shaked, I., Fisher, J., Mizrahi, T. and Schori, H., 2003, Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends Neurosci. 26: 297.PubMedGoogle Scholar
  195. Schwartz, M., Butovsky, O., Bruck, W. and Hanisch, U.K., 2006, Microglial phenotype: is the commitment reversible? Trends Neurosci. 29: 68.PubMedGoogle Scholar
  196. Shryock, J.C. and Belardinelli, L., 1997, Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am. J. Cardiol. 79: 2.PubMedGoogle Scholar
  197. Sitkovsky, M.V., 2003, Use of the A2A adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo. Biochem. Pharmacol. 65: 493.PubMedGoogle Scholar
  198. Sitkovsky, M.V. and Ohta, A., 2005, The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol. 26: 299.PubMedGoogle Scholar
  199. Sitkovsky, M.V., Lukashev, D., Apasov, S., Kojima, H., Koshiba, M., Caldwell, C., Ohta, A. and Thiel, M., 2004, Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu. Rev. Immunol. 22: 657.PubMedGoogle Scholar
  200. Sriram, K., Matheson, J.M., Benkovic, S.A., Miller, D.B., Luster, M.I. and O'Callaghan, J.P., 2006a, Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-α. FASEB J. 20: 670.PubMedGoogle Scholar
  201. Sriram, K., Miller, D.B. and O'Callaghan, J.P., 2006b, Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-α. J. Neurochem. 96: 706.PubMedGoogle Scholar
  202. Stone, T.W., 1985, Purines: Pharmacology and Physiological Roles. MacMillan, London.Google Scholar
  203. Streit, W.J., Walter, S.A. and Pennell, N.A., 1999, Reactive microgliosis. Prog. Neurobiol. 57: 563.PubMedGoogle Scholar
  204. Sullivan, G.W., Linden, J., Buster, B.L. and Scheld, W.M., 1999, Neutrophil A2A adenosine receptor inhibits inflammation in a rat model of meningitis: synergy with the type IV phosphodiesterase inhibitor, rolipram. J. Infect. Dis. 180: 1550.PubMedGoogle Scholar
  205. Svenningsson, P., Le Moine, C., Fisone, G. and Fredholm, B.B., 1999, Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog. Neurobiol. 59: 355.PubMedGoogle Scholar
  206. Takahashi, K., Rochford, C.D. and Neumann, H., 2005, Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201: 647.PubMedGoogle Scholar
  207. Tebano, M.T., Martire, A., Rebola, N., Pepponi, R., Domenici, M.R., Gro, M.C., Schwarzschild, M.A., Chen, J.F., Cunha, R.A. and Popoli, P., 2005, Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-D-aspartate effects. J. Neurochem. 95: 1188.PubMedGoogle Scholar
  208. Teismann, P. and Schulz, J.B., 2004, Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res. 318: 149.PubMedGoogle Scholar
  209. Tetzlaff, W., Schubert, P. and Kreutzberg, G.W., 1987, Synaptic and extrasynaptic localization of adenosine binding sites in the rat hippocampus. Neuroscience 21: 869.PubMedGoogle Scholar
  210. Togo, T., Akiyama, H., Iseki, E., Kondo, H., Ikeda, K., Kato, M., Oda, T., Tsuchiya, K. and Kosaka, K., 2002, Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J. Neuroimmunol. 124: 83.PubMedGoogle Scholar
  211. van Calker, D. and Biber, K., 2005, The role of glial adenosine receptors in neural resilience and the neurobiology of mood disorders. Neurochem. Res. 30: 1205.PubMedGoogle Scholar
  212. van Gool, W.A., Aisen, P.S. and Eikelenboom, P., 2003, Anti-inflammatory therapy in Alzheimer’s disease: is hope still alive? J. Neurol. 250: 788.PubMedGoogle Scholar
  213. Vezzani, A. and Granata, T., 2005, Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46: 1724.PubMedGoogle Scholar
  214. Villoslada, P., Hauser, S.L., Bartke, I., Unger, J., Heald, N., Rosenberg, D., Cheung, S.W., Mobley, W.C., Fisher, S. and Genain, C.P., 2000, Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J. Exp. Med. 191: 1799.PubMedGoogle Scholar
  215. Wang, T., Zhang, W., Pei, Z., Block, M., Wilson, B., Reece, J.M., Miller, D.S. and Hong, J.S., 2006, Reactive microgliosis participates in MPP+-induced dopaminergic neurodegeneration: role of 67 kDa laminin receptor. FASEB J. 20: 906.PubMedGoogle Scholar
  216. Wei, R. and Jonakait, G.M., 1999, Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming growth factor-β1 (TGF-β1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. J. Neuroimmunol. 95: 8.PubMedGoogle Scholar
  217. Weiner, H.L. and Selkoe, D.J., 2002, Inflammation and therapeutic vaccination in CNS diseases. Nature 420: 879.PubMedGoogle Scholar
  218. Wirkner, K., Assmann, H., Koles, L., Gerevich, Z., Franke, H., Norenberg, W., Boehm, R. and Illes, P., 2000, Inhibition by adenosine A2A receptors of NMDA but not AMPA currents in rat neostriatal neurons. Br. J. Pharmacol. 130: 259.PubMedGoogle Scholar
  219. Wirkner, K., Gerevich, Z., Krause, T., Gunther, A., Koles, L., Schneider, D., Norenberg, W. and Illes, P., 2004, Adenosine A2A receptor-induced inhibition of NMDA and GABAA receptor-mediated synaptic currents in a subpopulation of rat striatal neurons. Neuropharmacology 46: 994.PubMedGoogle Scholar
  220. Wu, D.C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D.K., Ischiropoulos, H. and Przedborski, S., 2002, Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22: 1763.PubMedGoogle Scholar
  221. Xu, K., Bastia, E. and Schwarzschild, M., 2005, Therapeutic potential of adenosine A2A receptor antagonists in Parkinson's disease. Pharmacol. Ther. 105: 267.PubMedGoogle Scholar
  222. Yoles, E., Hauben, E., Palgi, O., Agranov, E., Gothilf, A., Cohen, A., Kuchroo, V., Cohen, I.R., Weiner, H. and Schwartz, M., 2001, Protective autoimmunity is a physiological response to CNS trauma. J. Neurosci. 21: 3740.PubMedGoogle Scholar
  223. Yu, L., Huang, Z., Mariani, J., Wang, Y., Moskowitz, M. and Chen, J.F., 2004, Selective inactivation or reconstitution of adenosine A2A receptors in bone marrow cells reveals their significant contribution to the development of ischemic brain injury. Nat. Med. 10: 1081.PubMedGoogle Scholar
  224. Zandi, P.P., Anthony, J.C., Hayden, K.M., Mehta, K., Mayer, L., Breitner, J.C., Cache County Study Investigators, 2002, Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 59: 880.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Rodrigo A. Cunha
    • 1
  • Jiang-Fan Chen
    • 2
  • Michail V. Sitkovsky
    • 3
  1. 1.Center for Neuroscience and Cell Biology, Institute of Biochemistry, Faculty of MedicineUniversity of CoimbraPortugal
  2. 2.Department of NeurologyBoston University School of MedicineBostonUSA
  3. 3.New England Inflammation and Tissue Protection InstituteNortheastern UniversityBostonUSA

Personalised recommendations