| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
From the Neuroscience Research Unit (Drs. Grondin, Bédard, and Hadj Tahar, and L. Grégoire), Laval University Research Center, Quebec, Canada; and Pharmaceuticals Research and Development Center (Drs. Mori and Kase), Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan.
Address correspondence and reprint requests to Dr. Paul J. Bédard, Unité de Recherche en Neuroscience, Pavillon CHUL (RC 9800), 2705 Boul. Laurier, Ste-Foy, Québec, G1V 4G2, Canada.
BACKGROUND: Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so far, the A2A subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors might be used in PD.
OBJECTIVE: To evaluate the antiparkinsonian effect of a new selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.
METHODS: In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa–induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combination with L-dopa/benserazide (50/12.5 mg).
RESULTS: KW-6002 administered alone produced a dose-dependent antiparkinsonian response that reached the level of efficacy of L-dopa/benserazide but was less likely to reproduce dyskinesias in these animals. When co-administered, KW-6002 potentiated the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting the dyskinetic response.
CONCLUSION: Adenosine A2A receptor antagonists have antiparkinsonian effects of their own with a reduced propensity to elicit dyskinesias. They might therefore be useful agents in the treatment of PD.
This article has been cited by other articles:
|
|
 |
|
  R. A. Hodgson, R. Bertorelli, G. B. Varty, J. E. Lachowicz, A. Forlani, S. Fredduzzi, M. E. Cohen-Williams, G. A. Higgins, F. Impagnatiello, E. Nicolussi, et al. Characterization of the Potent and Highly Selective A2A Receptor Antagonists Preladenant and SCH 412348 [7-[2-[4-2,4-Difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in Rodent Models of Movement Disorders and Depression J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 294 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stacy, D. Silver, T. Mendis, J. Sutton, A. Mori, P. Chaikin, and N. M. Sussman A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease Neurology, June 3, 2008; 70(23): 2233 - 2240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cao, L. Liang, J. R. Hadcock, P. A. Iredale, D. A. Griffith, F. S. Menniti, S. Factor, J. T. Greenamyre, and S. M. Papa Blockade of Cannabinoid Type 1 Receptors Augments the Antiparkinsonian Action of Levodopa without Affecting Dyskinesias in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Rhesus Monkeys J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 318 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Xiao, E. Bastia, Y.-H. Xu, C. L. Benn, J.-H. J. Cha, T. S. Peterson, J.-F. Chen, and M. A. Schwarzschild Forebrain Adenosine A2A Receptors Contribute to L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice J. Neurosci., December 27, 2006; 26(52): 13548 - 13555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Calon, M. Dridi, O. Hornykiewicz, P. J. Bedard, A. H. Rajput, and T. Di Paolo Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias Brain, May 1, 2004; 127(5): 1075 - 1084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Fuxe, L.F. Agnati, K. Jacobsen, J. Hillion, M. Canals, M. Torvinen, B. Tinner-Staines, W. Staines, D. Rosin, A. Terasmaa, et al. Receptor heteromerization in adenosine A2A receptor signaling: Relevance for striatal function and Parkinson's disease Neurology, December 9, 2003; 61(90116): S19 - 23. [Abstract] [Full Text]
|
|
|
|
|
|
P. Jenner A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD Neurology, December 9, 2003; 61(90116): S32 - 38. [Abstract] [Full Text]
|
|
|
|
|
|
A. R. Carta, A. Pinna, E. Tronci, and M. Morelli Adenosine A2A and dopamine receptor interactions in basal ganglia of dopamine denervated rats Neurology, December 9, 2003; 61(90116): S39 - 43. [Abstract] [Full Text]
|
|
|
|
|
|
A. Mori and T. Shindou Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: A potential mechanism for the antiparkinsonian effects of A2A antagonists Neurology, December 9, 2003; 61(90116): S44 - 48. [Abstract] [Full Text]
|
|
|
|
|
|
J.-F. Chen, S. Fredduzzi, E. Bastia, L. Yu, R. Moratalla, E. Ongini, and M. A. Schwarzschild Adenosine A2A receptors in neuroadaptation to repeated dopaminergic stimulation: Implications for the treatment of dyskinesias in Parkinson's disease Neurology, December 9, 2003; 61(90116): S74 - 81. [Abstract] [Full Text]
|
|
|
|
|
|
H. Kase Industry forum: Progress in pursuit of therapeutic A2A antagonists: The adenosine A2A receptor selective antagonist KW6002: Research and development toward a novel nondopaminergic therapy for Parkinson's disease Neurology, December 9, 2003; 61(90116): S97 - 100. [Abstract] [Full Text]
|
|
|
|
|
|
T.N. Chase, F. Bibbiani, W. Bara-Jimenez, T. Dimitrova, and J.D. Oh-Lee Translating A2A antagonist KW6002 from animal models to parkinsonian patients Neurology, December 9, 2003; 61(90116): S107 - 111. [Abstract] [Full Text]
|
|
|
|
|
|
P. D. Alfinito, S.-P. Wang, L. Manzino, S. Rijhsinghani, G. D. Zeevalk, and P. K. Sonsalla Adenosinergic Protection of Dopaminergic and GABAergic Neurons against Mitochondrial Inhibition through Receptors Located in the Substantia Nigra and Striatum, Respectively J. Neurosci., November 26, 2003; 23(34): 10982 - 10987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Agnati, S. Ferre, C. Lluis, R. Franco, and K. Fuxe Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons Pharmacol. Rev., September 1, 2003; 55(3): 509 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Bara-Jimenez, A. Sherzai, T. Dimitrova, A. Favit, F. Bibbiani, M. Gillespie, M.J. Morris, M.M. Mouradian, and T.N. Chase Adenosine A2A receptor antagonist treatment of Parkinson's disease Neurology, August 12, 2003; 61(3): 293 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Hauser, J. P. Hubble, D. D. Truong, and the Istradefylline US-001 Study Group Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD Neurology, August 12, 2003; 61(3): 297 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Valenti, M. J. Marino, M. Wittmann, E. Lis, A. G. DiLella, G. G. Kinney, and P. J. Conn Group III Metabotropic Glutamate Receptor-Mediated Modulation of the Striatopallidal Synapse J. Neurosci., August 6, 2003; 23(18): 7218 - 7226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Kim and R. D. Palmiter Adenosine receptor blockade reverses hypophagia and enhances locomotor activity of dopamine-deficient mice PNAS, February 4, 2003; 100(3): 1346 - 1351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Schwarzschild, J.-F. Chen, and A. Ascherio Caffeinated clues and the promise of adenosine A2A antagonists in PD Neurology, April 23, 2002; 58(8): 1154 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Fredduzzi, R. Moratalla, A. Monopoli, B. Cuellar, K. Xu, E. Ongini, F. Impagnatiello, M. A. Schwarzschild, and J.-F. Chen Persistent Behavioral Sensitization to Chronic L-DOPA Requires A2A Adenosine Receptors J. Neurosci., February 1, 2002; 22(3): 1054 - 1062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Shindou, A. Mori, H. Kase, and M. Ichimura Adenosine A2A receptor enhances GABAA-mediated IPSCs in the rat globus pallidus J. Physiol., April 15, 2001; 532(2): 423 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Chen, K. Xu, J. P. Petzer, R. Staal, Y.-H. Xu, M. Beilstein, P. K. Sonsalla, K. Castagnoli, N. Castagnoli Jr, and M. A. Schwarzschild Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson's Disease J. Neurosci., May 15, 2001; 21(10): RC143 - RC143. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
