Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys
Identifieur interne : 003839 ( Main/Exploration ); précédent : 003838; suivant : 003840Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys
Auteurs : R. Grondin [Canada] ; P. J. Bedard [Canada] ; A. Hadj Tahar [Canada] ; L. Gregoire [Canada] ; A. Mori [Japon] ; H. Kase [Japon]Source :
- Neurology [ 0028-3878 ] ; 1999.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Singe.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (adverse effects), A2 Adenosine receptor, Animal, Animal model, Animals, Antagonist, Antiparkinson agent, Brain (drug effects), Chemotherapy, Female, Levodopa (pharmacology), Levodopa (therapeutic use), Locomotion (drug effects), Macaca fascicularis, Monkey, Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (drug therapy), Parkinson disease, Purinergic P1 Receptor Antagonists, Purines (pharmacology), Purines (therapeutic use), Receptor, Adenosine A2A, Treatment.
- MESH :
- chemical , adverse effects : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
- chemically induced : Parkinson Disease, Secondary.
- drug effects : Brain, Locomotion.
- drug therapy : Parkinson Disease, Secondary.
- chemical , pharmacology : Levodopa, Purines.
- chemical , therapeutic use : Levodopa, Purines.
- Animals, Female, Macaca fascicularis, Purinergic P1 Receptor Antagonists, Receptor, Adenosine A2A.
Abstract
Article abstract-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.
Affiliations:
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Grondin</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, Laval University Research Center</s1><s2>Quebec</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, Laval University Research Center</s1><s2>Quebec</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Hadj Tahar, A" sort="Hadj Tahar, A" uniqKey="Hadj Tahar A" first="A." last="Hadj Tahar">A. Hadj Tahar</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, Laval University Research Center</s1><s2>Quebec</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Gregoire, L" sort="Gregoire, L" uniqKey="Gregoire L" first="L." last="Gregoire">L. Gregoire</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, Laval University Research Center</s1><s2>Quebec</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Mori, A" sort="Mori, A" uniqKey="Mori A" first="A." last="Mori">A. Mori</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Pharmaceuticals Research and Development Center, Kyowa Hakko Kogyo Co., Ltd.</s1><s2>Tokyo</s2><s3>JPN</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Japon</country><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Kase, H" sort="Kase, H" uniqKey="Kase H" first="H." last="Kase">H. Kase</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Pharmaceuticals Research and Development Center, Kyowa Hakko Kogyo Co., Ltd.</s1><s2>Tokyo</s2><s3>JPN</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Japon</country><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author></analytic><series><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno><imprint><date when="1999">1999</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (adverse effects)</term><term>A2 Adenosine receptor</term><term>Animal</term><term>Animal model</term><term>Animals</term><term>Antagonist</term><term>Antiparkinson agent</term><term>Brain (drug effects)</term><term>Chemotherapy</term><term>Female</term><term>Levodopa (pharmacology)</term><term>Levodopa (therapeutic use)</term><term>Locomotion (drug effects)</term><term>Macaca fascicularis</term><term>Monkey</term><term>Parkinson Disease, Secondary (chemically induced)</term><term>Parkinson Disease, Secondary (drug therapy)</term><term>Parkinson disease</term><term>Purinergic P1 Receptor Antagonists</term><term>Purines (pharmacology)</term><term>Purines (therapeutic use)</term><term>Receptor, Adenosine A2A</term><term>Treatment</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term><term>Locomotion</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Levodopa</term><term>Purines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Levodopa</term><term>Purines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Female</term><term>Macaca fascicularis</term><term>Purinergic P1 Receptor Antagonists</term><term>Receptor, Adenosine A2A</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Parkinson maladie</term><term>Antagoniste</term><term>Récepteur adénosinique A2</term><term>Antiparkinsonien</term><term>Chimiothérapie</term><term>Traitement</term><term>Animal</term><term>Singe</term><term>Modèle animal</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Singe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Article abstract-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 A<sub>2A</sub> subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D<sub>2</sub> receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A<sub>2A</sub> receptors might be used in PD. Objective: To evaluate the antiparkinsonian effect of a new selective adenosine A<sub>2A</sub> 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 A<sub>2A</sub> 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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Japon</li></country><settlement><li>Tokyo</li></settlement></list><tree><country name="Canada"><noRegion><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name></noRegion><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name><name sortKey="Gregoire, L" sort="Gregoire, L" uniqKey="Gregoire L" first="L." last="Gregoire">L. Gregoire</name><name sortKey="Hadj Tahar, A" sort="Hadj Tahar, A" uniqKey="Hadj Tahar A" first="A." last="Hadj Tahar">A. Hadj Tahar</name></country><country name="Japon"><noRegion><name sortKey="Mori, A" sort="Mori, A" uniqKey="Mori A" first="A." last="Mori">A. Mori</name></noRegion><name sortKey="Kase, H" sort="Kase, H" uniqKey="Kase H" first="H." last="Kase">H. Kase</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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