Skip to main content
SpringerLink
Log in

Adenosine A2A receptor antagonists: Potential therapeutic and neuroprotective effects in parkinson’s disease

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

The most effective treatment of Parkinson’s disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenyl-alanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term, effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A2A receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A2A antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4, 3-e)-l,2,4-triazolo(l,5-c)pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Foslike-immunoreactivity in neurons of the lesioned striatum. Likewise, other A2A receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropy1-7-methylxan-thine] (KF 17837) and [E-1,3-diety1-8(3,4-dimethox-ystyry1-7-methy1-3,7-dhydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A2A receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A2A antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the (1-methy1-4-pheny1-1,2,3,6-tetrahydropyridine) (MPTP) model of PD. Adenosine A2A receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AC:

adenylate cyclase

AD:

adenosine

cAMP:

cyclic adenosine monophosphate

CGS 15943:

5-amino-9-chloro-2-(2-furyl)-l,2,4-triazolo[1,5-c]quinazoline

CGS 21680:

2-[4-(2-carbonyl-ethyl)-phenethylammo]-5′-N-ethyl-carboxamidoadenosine

CP:

caudate-putamen

CP 66713:

4-amino-l-phenyl-[l,2,4]-triazolo[4,3-a]quinoxaline

CSC:

8-(3-chlorostyryl)caffeine

DA:

dopamine

DMPX:

3,7-dimethyl-l-propargylxanthine

DYN:

dynorphin

ENK:

enkephalin

GABA:

γ-aminobutyric acid

Glu:

glutamic acid

GP:

globus pallidus

2-HE-NECA:

2-hexyl-5′-N-ethylcarbox-amidoadenosine

KF17837:

(E)-l,3-dipropyl-8-(3,4-dimethox-ystyryl)-7-methyl-3,7-dihydro-lH-purine-2,6-dione

KW 6002:

(E)-l,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-lH-purine-2,6-dione

L-DOPA:

L-3,4-dihydroxy-phenylalanine

MPTP:

l-methyl-4-phenyl-l,2,3,6-tetrahydro-pyridine

6-OHDA:

6-hydroxydopamine

PD:

Parkinson’s disease

SCH 58261:

5-amino-7-(2-phenylethyl-2-(2-furyl)-pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c ]pyrimidine

SNr:

substantia nigra pars reticulata

SP:

substance P

STN:

subthalamic nucleus

Th:

thalamus

ZM 241385:

4-(2-[7-amino-2-(2-furyl)l,2,4-triazolo[2,3-a][l,3,5]triazin-5-ylamino]ethylphenol

References

  • Aoyama, S., Kase, H. and Borelli, E. (2000) “Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist”,J. Neurosci. 20, 5848–5852.

    PubMed  CAS  Google Scholar 

  • Barraco, R.A., Martens, K.A., Parizon, M. and Normile, H.J. (1993) “Adenosine A2a receptors in the nucleus accum-bens mediate locomotor depression”,Brain Res. Bull. 31, 397–404.

    Article  PubMed  CAS  Google Scholar 

  • Bona, E., Aden, U., Gilland, E., Fredholm, B.B. and Hagberg, H. (1997) “Neonatal cerebral hypoxia ischemia: the effect of adenosine receptor antagonists”,Neuropharmacology 36, 1327–1338.

    Article  PubMed  CAS  Google Scholar 

  • Casas, M., Ferre, S., Cobos, A., Grau, J.N. and Jane, F. (1989) “Relationship between rotational behaviour induced by apomorphine and caffeine in rats with unilateral lesion of the nigrostriatal pathway”,Neuropharmacology 28, 407–409.

    Article  PubMed  CAS  Google Scholar 

  • Chen, J.F., Huang, Z., Ma, J., Zhu, J.M., Moratalla, R., Standaert, D., Moskowitz, M.A., Fink, J.S. and Schwarzs-child, M.A. (1999) “A2A adenosine receptors deficiency attenuate brain injury induced by transient focal ischemia in mice”,J. Neurosci. 19, 9192–9200.

    PubMed  CAS  Google Scholar 

  • Chen, J.F., Moratalla, R., Standaert, D., Impagnatiello, F., Grandy, D.K., Cuellar, B., Rubistein, M., Beilstein, M., Hackett, E., Fink, J.S., Low, M.J., Ongini, E. and Schwarzschild, M.A. (2001a) “The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice”,Proc. Natl. Acad. Sci. 98, 1970–1975.

    Article  PubMed  CAS  Google Scholar 

  • Chen, J.F., Xu, K., Petzer, J.P., Staal, R., Xu, Y-H., Beilstein, M. A., Sonsalla, P.K., Castagnoli, K., Castagnoli, Jr, N. and Schwarzschild, Jr, M.A. (2001b) “Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson’s Disease”,J. Neurosci. 21, 143.

    Google Scholar 

  • Dasgupta, S., Ferre, S., Kull, B., Hedlund, P.B., Finnman, U.B., Ahlberg, S., Arenas, E., Fredholm, B.B. and Fuxe, K. (1996) “Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected cells”,Eur. J. Pharmacol. 316, 325–331.

    Article  PubMed  CAS  Google Scholar 

  • Dixon, A.K., Widdwson, P.J. and Richardson, P.J. (1997) “Desensitisation of the adenosine Ai receptor by the A2A receptor in the striatum”,J.Neurochem. 69, 315–321.

    PubMed  CAS  Google Scholar 

  • Durcan, M.J. and Morgan, P.F. (1989) “Evidence for adenosine A2 receptor involvement in the hypomobility effects of adenosine analogues in mice”,Eur. J. Pharmacol. 168, 285–290.

    Article  PubMed  CAS  Google Scholar 

  • Fenu, S. and Morelli, M. (1998) “Motor stimulant effects of caffeine in 6-hydroxydopamine-lesioned rats are dependent on previous stimulation of dopamine receptors: a different role of Dj and D2 receptors”,Eur. Neurosci. 10, 1878–1884.

    Article  CAS  Google Scholar 

  • Fenu, S., Pinna, A., Ongini, E. and Morelli, M. (1997) “Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats”,Eur. J. Pharmacol. 321, 143–147.

    Article  PubMed  CAS  Google Scholar 

  • Ferre, S. (1997) “Adenosine-dopamine interactions in the ventral striatum. Implications for the treatment of schizophrenia.”,Psychopharmacology 133, 107–120.

    Article  PubMed  CAS  Google Scholar 

  • Ferre, S., Von Euler, G., Johansson, B., Fredholm, B.B. and Fuxe, K. (1991) “Stimulation of high affinity adenosine A-2 receptors decreases the affinity of dopamine D-2 receptors in rat striatal membranes”,Proc. Natl. Acad. Sci. USA. 88, 7238–7241.

    Article  PubMed  CAS  Google Scholar 

  • Ferre, S., Fredholm, B.B., Morelli, M., Popoli, P. and Fuxe, K. (1997) “Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia”,Trend Neurosci. 20, 482–486.

    Article  PubMed  CAS  Google Scholar 

  • Fink, J.S., Weaver, D.R., Rivkees, S.A., Peterfreund, R.A., Pollack, A.E., Adler, E.M. and Reppert, S.M. (1992) “Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum”,Mol. Brain Res. 14, 186–190.

    Article  PubMed  CAS  Google Scholar 

  • Fredholm, B.B., Ijzerman, A.P., Jacobson, K.A., Linden, J. and Stiles, G.L. (1998) “Adenosine receptors”, IUPHAR Compendium of Receptor Characterization and Classification (IUPHAR Media, London), pp. 48–57.

    Google Scholar 

  • Fredholm, B.B., Battig, K., Holmen, J., Nehlig, A. and Zvartau, E.E. (1999) “Actions of caffeine in the brain with special reference to factors that contribute to its widespread use”,Pharmacol. Rev. 51, 83–133.

    PubMed  CAS  Google Scholar 

  • Fuxe, K. and Ungerstedt, U. (1974) “Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with DOPA and dopamine receptor agonists”,Med. Biol. 52, 48–54.

    PubMed  CAS  Google Scholar 

  • Gao, Y. and Phillis, J.W. (1994) “CGS 15943, an adenosine A2 receptor antagonist, reduces cerebral ischaemic injury in the Mongolian gerbil”,Life Sci. 55, 61–65.

    Article  Google Scholar 

  • Garrett, B.E. and Griffiths, R.R. (1997) “The role of dopamine in the behavioral effects of caffeine in animals and humans”,Pharmacol. Biochem. Behav. 57, 533–541.

    Article  PubMed  CAS  Google Scholar 

  • Garrett, B.E. and Holtzman, S.G. (1994a) “Da and D2 dopamine receptor antagonists block caffeine-induced stimulation of locomotor activity in rats”,Pharmacol. Biochem. Behav. 47, 89–94.

    Article  PubMed  CAS  Google Scholar 

  • Garrett, B.E. and Holtzman, S.G. (1994b) “Caffeine cross-tolerance to selective dopamine Dx and D2 receptor agonists but not to their synergistic interaction”,Eur. J. Pharmacol. 262, 65–75.

    Article  PubMed  CAS  Google Scholar 

  • Gerfen, C.R., Engber, T.M., Mahan, L.C., Susel, Z., Chase, T.N., Monsma, Jr, F.J. and Sibley, Jr, D.R. (1990) “Dl and D2 dopamine receptor-regulated gene expression of striato-nigral and striatopallidal neurons”,Science 250, 1429–1432.

    Article  PubMed  CAS  Google Scholar 

  • Griebel, G., Saffroy-Spittler, M., Misslin, R., Remmy, D., Vogel, E. and Bourguignon, J.J. (1991) “Comparison of the behavioral effects of an adenosine Al/A2-receptor antagonist, CGS 5943A and an Al-selective antagonist, DPCPX”,Psychopharmacology 103, 541–544.

    Article  PubMed  CAS  Google Scholar 

  • Grondin, R., Bedard, P. J., Hadj Tahar, A., Gregoire, L., Mori, A. and Kase, H. (1999) “Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys”,Neurology 52, 1673–1677.

    PubMed  CAS  Google Scholar 

  • Hauber, W., Nagel, J., Sauer, R. and Muller, C.E. (1998) “Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen”,Neroreport 9, 1803–1806.

    CAS  Google Scholar 

  • Heffner, T.G., Wiley, J.N., Williams, A.E., Bruns, R.F., Coughenour, L.L. and Downs, D.A. (1989) “Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice”,Psychopharmacology 98, 31–37.

    Article  PubMed  CAS  Google Scholar 

  • Henry, B., Crossman, A.R. and Brotchie, J.M. (1998) “Characterisation of enhanced behavioral responses to L-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease”,Exp. Neurol. 151, 334–342.

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Marschitz, M., Casas, M. and Ungerstedt, U. (1988) “Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses”,Psychopharmacology 94, 38–45.

    Article  PubMed  CAS  Google Scholar 

  • Higashi, H., Marwaha, A.S., Memo, J.R. and Winn, H.R. (2000) “Correlation between hippocampal injury and neurobe-havior following normo- and hyperglycemic cerebral ischemia, effect of theophylline and ZM241385”,Drug Dev. Res. 50, 71–092.

    Google Scholar 

  • Holtzman, S. and G,. (1991) “CGS 15943, a non xanthine adenosine receptor antagonist: effects on locomotor activity of non tolerant and caffeine-tolerant rats”,Life Sci. 49, 1563–1570.

    Article  PubMed  CAS  Google Scholar 

  • Hurley, M.J., Mash, D.C. and Jenner, P. (2000) “Adenosine A2A receptor mRNA expression in Parkinson’s disease”,Neurosci. Lett. 291, 54–58.

    Article  PubMed  CAS  Google Scholar 

  • Jarvis, M.F. and Williams, M. (1989) “Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]CGS 21680”,Eur. J. Pharmacol. 168, 243–246.

    Article  PubMed  CAS  Google Scholar 

  • Jiang, H., Jackson-Lewis, V., Muthane, U., Dollison, A., Ferreira, M., Espinosa, A., Parsons, B. and Przedborski, S. (1993) “Adenosine receptor antagonists potentiate dopamine receptor agonist-induced rotational behavior in 6-hydroxydopamine-lesioned rats”,Brain Res. 613, 347–351.

    Article  PubMed  CAS  Google Scholar 

  • Jones, PA., Smith, R.A. and Stone, T.W. (1998a) “Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist”,Brain Res. 800, 328–335.

    Article  PubMed  CAS  Google Scholar 

  • Jones, P.A., Smith, R.A. and Stone, T.W. (1998b) “Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists”,Neuroscience 85, 229–237.

    Article  PubMed  CAS  Google Scholar 

  • Josselyn, S.A. and Beninger, R.J. (1991) “Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine”,Pharmacol. Biochem. Behav. 39, 97–103.

    Article  PubMed  CAS  Google Scholar 

  • Kafka, S.H. and Corbett, R. (1996) “Selective adenosine A2A receptor/dopamine D2 receptor interactions in animal models of schizophrenia”,Eur. Pharmacol. 295, 147–154.

    Article  CAS  Google Scholar 

  • Kanda, T, Shiozaki, S., Shimada, J., Suzuki, F. and Nakamura, J. (1994) “KF17837: a novel selective adenosine A2A antagonist with anticataleptic activity”,Eur. Pharmacol. 256, 263–268.

    Article  CAS  Google Scholar 

  • Kanda, T., Jackson, M.J., Smith, L.A., Pearce, R.K.B., Nakamura, J., Kase, H., Kuwana, Y. and Jenner, P. (1998) “Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys”,Ann. Neurol. 43, 507–513.

    Article  PubMed  CAS  Google Scholar 

  • Kartzinel, R., Shoulson, I. and Calne, D.B. (1976) “Studies with bromocriptine III. Concomitant administration of caffeine to patients with idopathic parkinsonism”,Neurology 26, 741–743.

    PubMed  CAS  Google Scholar 

  • Kirk, LP. and Richardson, P.J. (1994) “Adenosine A2a receptor-mediated modulation of striatal [3H]GABA and [3H]Acetylcholine release”,J. Neurochem 62, 960–966.

    Article  PubMed  CAS  Google Scholar 

  • Kurokawa, M, Kirk, LP., Kirkpatric, K.A., Kase, H. and Richardson, P.J. (1994) “Inhibition by KF 17837 of adenosine receptor-mediated modulation of striatal GABA and ACh release”,Br. J. Pharmacol. 113, 43–48.

    PubMed  CAS  Google Scholar 

  • von Lubitz, D.J.K.E., Lin, R.C.S. and Jacobson, K.A. (1995) “Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist”,Eur. J. Pharmacol. 287, 295–302.

    Article  Google Scholar 

  • Mally, J. and Stone, T.W. (1996) “Potential role of adenosine antagonist therapy in pathological tremor disorders”,Pharmacol. Ther. 72, 243–250.

    Article  PubMed  CAS  Google Scholar 

  • Mandhane, S.N., Chopde, C.T. and Ghosh, A.K. (1997) “Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats”,Eur. J. Pharmacol. 328, 135–141.

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Mir, M.I., Probst, A. and Palacios, J.M. (1991) “Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease”,Neuroscience 42, 697–706.

    Article  PubMed  CAS  Google Scholar 

  • de Mendonca, A., Sebastiao, A.M. and Ribeiro, J.A. (2000) “Adenosine: does it have a neuroprotective role after all?”,Brain Res. Rev. 33, 258–274.

    Article  PubMed  Google Scholar 

  • Le Moine, C, Svenningsson, P., Fredholm, B.B. and Bloch, B. (1997) “Dopamine-adenosine interactions in the striatum and globus pallidum: inhibition of striatopallidal neurons through either D2 or A2A receptors enhances Dt receptor-mediated effects on c-foc expression”,J. Neurosci. 17, 8038–8048.

    PubMed  Google Scholar 

  • Monopoli, A., Lozza, G., Forlani, A., Mattavelli, A. and Ongini, E. (1998) “Blockade of A2A adenosine receptors by SCH 58261 results in neuroprotective effect in cerebral ischemia in mice”,NeuroReport 9, 3955–3959.

    Article  PubMed  CAS  Google Scholar 

  • Monopoli, A., Impagnatiello, R, Bastia, E., Fredduzzi, S. and Ongini, E. (2000) “Anti-parkinsonian effects of selective A2A adenosine receptor antagonists in relevant rodent models”,Drug Dev. Res. 50, 70–87.

    Google Scholar 

  • Morelli, M., Fenu, S., Pinna, A. and Di Chiara, G. (1994) “Adenosine A2 receptors interact negatively with dopamine Di and D2 receptors in unilaterally 6-hydroxy-dopamine-lesioned rats”,Eur. J. Pharmacol. 251, 21–25.

    Article  PubMed  CAS  Google Scholar 

  • Morelli, M., Pinna, A., Wardas, J. and Di Chiara, G. (1995) “Adenosine A2 receptors stimulate c-fos expression in striatal neurons of 6-hydroxydopamine-lesioned rats”,Neuroscience 67, 49–55.

    Article  PubMed  CAS  Google Scholar 

  • Mori, A., Shindou, T., Ichimura, M., Nonaka, H. and Kase, H. (1996) “The role of adenosine A2A receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons”,J. Neurosci. 16, 605–611.

    PubMed  CAS  Google Scholar 

  • Olah, M. and Stiles, G.L. (2000) “The role of receptor structure in determining adenosine receptor activity”,Pharmacol. & Therap. 85, 55–75.

    Article  CAS  Google Scholar 

  • Ongini, E. and Fredholm, B.B. (1996) “Pharmacology of adenosine A2A receptors”,Trends Pharmacol. Sci. 17, 364–372.

    Article  PubMed  CAS  Google Scholar 

  • Ongini, E. and Schubert, P. (1998) “Neuroprotection induced by stimulating Al or blocking A2A adenosine receptors: an apparent paradox”,Drug Dev. Res. 45, 387–393.

    Article  CAS  Google Scholar 

  • Ongini, E., Dionisotri, S., Morelli, M., Ferre, S., Svenningsson, P., Fuxe, K. and Fredholm, B.B. (1996) “Neuropharmacology of the adenosine A2A receptors”,Drug Dev. Res. 39, 450–460.

    Article  CAS  Google Scholar 

  • O’Regan, M.H., Simpson, R.E., Perkins, L.M. and Phillis, J.W. (1992) “The selective A2 agonist CGS 21680 enhances excitatory transmitter amino acid release from the ischemic rat cerebral cortex”,Neurosci. Lett. 138, 169–172.

    Article  PubMed  CAS  Google Scholar 

  • Phillis, J.W. (1995) “The effects of selective Aj and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil”,Brain Res. 705, 79–84.

    Article  PubMed  CAS  Google Scholar 

  • Pinna, A., Di Chiara, G., Wardas, J. and Morelli, M. (1996) “Blockade of A2a adenosine receptors positively modulates turning behaviour and c-Fos expression induced byDt agonists in dopamine-denervated rats”,Eur. J. Neurosci. 8, 1176–1181.

    Article  PubMed  CAS  Google Scholar 

  • Pinna, A., Fenu, S. and Morelli, M. (2001) “Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats”,Synapse 39, 233–238.

    Article  CAS  Google Scholar 

  • Pollack, A.E. and Fink, J.S. (1996) “Synergistic interaction between an adenosine antagonist and aD1 dopamine agonist on rotational behavior and striatal c-Fos induction in 6-hydroxydopamine-lesioned rats”,Brain Res. 743, 124–130.

    Article  PubMed  CAS  Google Scholar 

  • Popoli, P., Pezzola, A., Reggio, R. and Scotti de Carolis, A. (1994) “Modulation of striatal adenosine Al and A2 receptors induces rotational behavior in response to dopaminergic stimulation in intact rats”,Eur. J. Pharmacol. 257, 21.

    Article  PubMed  CAS  Google Scholar 

  • Popoli, P., Betto, P., Reggio, R. and Ricciarello, G. (1995) “Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats”,Eur. J. Pharmacol. 287, 215–217.

    Article  PubMed  CAS  Google Scholar 

  • Richardson, P.J., Kase, H. and Jenner, P.G. (1997) “Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson’s disease”,Trends Pharmacol. Sci. 18, 338–344.

    PubMed  CAS  Google Scholar 

  • Rimondini, R., Ferre, S., Ogren, S.O. and Fuxe, K. (1997) “Adenosine A2A agonists: a potential new type of atypical antipsychotics”,Neuropsychopharmacology 17, 81–91.

    Article  Google Scholar 

  • Rosin, D.L., Robeva, A., Woodard, R.L., Guyenet, P.G. and Linden, J. (1998) “Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system”,J. Comp. Neurol. 401, 163–186.

    Article  PubMed  CAS  Google Scholar 

  • Ross, G.W., Abbott, R.D., Petrovitch, H., Morens, D.M., Grandinetti, A., Tung, K.-H., Tanner, CM., Masaki, K.H., Blanchette, PL., Curb, J.D., Popper, J.S. and White, L.R. (2000) “Association of coffee and caffeine intake with the risk of Parkinson disease”,J. Med. American Ass. 283, 2674–2679.

    Article  CAS  Google Scholar 

  • Rudolphi, K., Schubert, P., Parkinson, F.E. and Fredholm, B.B. (1992) “Neuroprotective role of adenosine in cerebral ischaemia”,Trends Pharmacol. Sci. 13, 439–445.

    Article  PubMed  CAS  Google Scholar 

  • Schenk, S., Valadez, A., Horger, B.A., Snow, S. and Wellman, P.J. (1994) “Interaction between caffeine and cocaine in tests of self-administration”,Behav. Pharmacol. 5, 153–158.

    Article  PubMed  CAS  Google Scholar 

  • Schiffmann, S.N., Jacobs, O. and Vanderhaeghen, J.J. (1991) “The striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons. An in situ hybridization histochemistry study”,J. Neurochem. 57, 1062–1067.

    Article  PubMed  CAS  Google Scholar 

  • Sebastiao, A.M. and Ribeiro, J.A. (1996) “Adenosine A2A receptor-mediated excitatory actions on the nervous system”,Prog. Neurobiol. 48, 167–189.

    Article  PubMed  CAS  Google Scholar 

  • Sebastiao, A.M. and Ribeiro, J.A. (2000) “Fine-tuning neuromodulation by adenosine”,Trends Pharmacol Sci. 21, 341–346.

    Article  PubMed  CAS  Google Scholar 

  • Sheardown, M.J. and Rnutsen, L.J.S. (1996) “Unexpected neuroprotection observed with the adenosine A2A receptor agonist CGS 21680”,Drug Dev. Res. 39, 108–114.

    Article  CAS  Google Scholar 

  • Shiozaki, S., Ichikawa, S., Nakamura, J., Kitamura, S., Yamada, K. and Kuwana, Y. (1999) “Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP”,Psychopharmacology 147, 90–95.

    Article  PubMed  CAS  Google Scholar 

  • Shoulson, I. and Chase, T. (1975) “Caffeine and the antiparkinsonian response to levodopa or pirebidil”,Neurology 25, 722–724.

    PubMed  CAS  Google Scholar 

  • Simpson, R.E., O’Regan, M.H., Perkins, L.M. and Phillis, J.W. (1992) “Excitatory transmitter amino acid release from the ischemic rat cerebral cortex: effects of adenosine receptor agonists and antagonists”,J. Neurochem. 58, 1683–1690.

    Article  PubMed  CAS  Google Scholar 

  • Stromberg, I., Popoli, P., Muller, C, Feree, S. and Fuxe, J. (2000) “Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptor regulation in the rat dopamine-denervated striatum”,Eur. J. Neurosci. 12, 4033–4037.

    Article  PubMed  CAS  Google Scholar 

  • Stone, T.W. and Behan, W.M.H. (2000) “Adenosine receptors, kynurenines and neuroprotection”,Drug Dev. Res. 50, 15.

    Google Scholar 

  • Svenningsson, P., Hall, H., Sedvall, G. and Fredholm, B.B. (1997a) “Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study”,Synapse 27, 322–335.

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson, P., Nomikos, G.G., Qngini, E. and Fredholm, B.B. (1997b) “Antagonism of adenosine A2A receptors underlies the behavioural activating effect of caffeine and is associated with reduced expression of messenger RNA for NGFI-A and NGFI-B in caudate-putamen and nucleus accumbens”,Neuroscience 79, 753–764.

    Article  PubMed  CAS  Google Scholar 

  • Ungerstedt, U. (1971) “Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigros-triatal dopamine system”,Acta. Physiol. Scand. 367, 69–74.

    CAS  Google Scholar 

  • Vellucci, S.V., Sirinathsinghji, D.J.S. and Richardson, P.J. (1993) “Adenosine A2 receptor regulation of apomorphine-induced turning in rats with unilateral striatal dopamine denervation”,Psychopharmacology 111, 383–388.

    Article  PubMed  CAS  Google Scholar 

  • Zahniser, N.R., Simosky, J.K., Mayfield, R.D., Negri, C.A., Hanania, T., Larson, G.A., Kelly, M.A., Grandy, D.K., Rubinstein, M., Low, M.J. and Fredholm, B.B. (2000) “Functional uncoupling of adenosine A2A receptors and reduced response to caffeine in mice lacking dopamine D2 receptors”,J. Neurosci. 20, 5949–5957.

    PubMed  CAS  Google Scholar 

  • Zocchi, C, Ongini, E., Conti, A., Monopoli, A., Negretti, A., Baraldi, P.G. and Dionisotti, S. (1996) “The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2A adenosine receptor antagonist”,J. Pharmacol. Exp. Ther. 276, 389–404.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Toxicology, University of Cagliari, Palazzo delle Scienze, Via Ospedale 72, 09124, Cagliari, Italy

    M. Morelli

  2. Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland

    J. Wardas

Authors
  1. M. Morelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Wardas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Wardas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morelli, M., Wardas, J. Adenosine A2A receptor antagonists: Potential therapeutic and neuroprotective effects in parkinson’s disease. neurotox res 3, 545–556 (2001). https://doi.org/10.1007/BF03033210

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033210

Keywords

Search

Navigation