Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders
Identifieur interne : 001C85 ( Main/Exploration ); précédent : 001C84; suivant : 001C86Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders
Auteurs : Robert A. Hodgson [États-Unis] ; Paul J. Bedard [Canada] ; Geoffrey B. Varty [États-Unis] ; Tatiana M. Kazdoba [États-Unis] ; Therese Di Paolo [Canada] ; Michael E. Grzelak [États-Unis] ; Annamarie J. Pond [États-Unis] ; Abdallah Hadjtahar [Canada] ; Nancy Belanger [Canada] ; Laurent Gregoire [Canada] ; Aurelie Dare [Canada] ; Bernard R. Neustadt [États-Unis] ; Andrew W. Stamford [États-Unis] ; John C. Hunter [États-Unis]Source :
- Experimental neurology : (Print) [ 0014-4886 ] ; 2010.
Descripteurs français
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Abstract
Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D2 receptors by antipsychotics, respectively. Adenosine A2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D2 receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A2A receptor activation contributes to the overdrive of the indirect pathway. A2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.
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Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Therese" last="Di Paolo">Therese Di Paolo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL)</s1><s2>Quebec</s2><s3>CAN</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Grzelak, Michael E" sort="Grzelak, Michael E" uniqKey="Grzelak M" first="Michael E." last="Grzelak">Michael E. Grzelak</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. 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Hodgson</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Bedard, Paul J" sort="Bedard, Paul J" uniqKey="Bedard P" first="Paul J." last="Bedard">Paul J. Bedard</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University</s1><s2>Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Varty, Geoffrey B" sort="Varty, Geoffrey B" uniqKey="Varty G" first="Geoffrey B." last="Varty">Geoffrey B. Varty</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Kazdoba, Tatiana M" sort="Kazdoba, Tatiana M" uniqKey="Kazdoba T" first="Tatiana M." last="Kazdoba">Tatiana M. Kazdoba</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Therese" last="Di Paolo">Therese Di Paolo</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL)</s1><s2>Quebec</s2><s3>CAN</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Grzelak, Michael E" sort="Grzelak, Michael E" uniqKey="Grzelak M" first="Michael E." last="Grzelak">Michael E. Grzelak</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Pond, Annamarie J" sort="Pond, Annamarie J" uniqKey="Pond A" first="Annamarie J." last="Pond">Annamarie J. Pond</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurobiology, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Hadjtahar, Abdallah" sort="Hadjtahar, Abdallah" uniqKey="Hadjtahar A" first="Abdallah" last="Hadjtahar">Abdallah Hadjtahar</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University</s1><s2>Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Belanger, Nancy" sort="Belanger, Nancy" uniqKey="Belanger N" first="Nancy" last="Belanger">Nancy Belanger</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University</s1><s2>Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Gregoire">Laurent Gregoire</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University</s1><s2>Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL)</s1><s2>Quebec</s2><s3>CAN</s3><sZ>5 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Dare, Aurelie" sort="Dare, Aurelie" uniqKey="Dare A" first="Aurelie" last="Dare">Aurelie Dare</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Neuroscience Research Unit, Laval University Medical Center, CHUL Pavilion and Faculty of Medicine, Laval University</s1><s2>Quebec</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ><sZ>10 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Neustadt, Bernard R" sort="Neustadt, Bernard R" uniqKey="Neustadt B" first="Bernard R." last="Neustadt">Bernard R. Neustadt</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Chemical Research, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Stamford, Andrew W" sort="Stamford, Andrew W" uniqKey="Stamford A" first="Andrew W." last="Stamford">Andrew W. Stamford</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Chemical Research, Merck and Co. Inc., 2015 Galloping Hill Road</s1><s2>Kenilworth, NJ 07033</s2><s3>USA</s3><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Kenilworth, NJ 07033</wicri:noRegion></affiliation></author><author><name sortKey="Hunter, John C" sort="Hunter, John C" uniqKey="Hunter J" first="John C." last="Hunter">John C. Hunter</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Neurobiology, Merck and Co. Inc. 770 Sumneytown Pike</s1><s2>West Point, PA 19486</s2><s3>USA</s3><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>West Point, PA 19486</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine</term><term>Animal</term><term>Biological receptor</term><term>Extrapyramidal syndrome</term><term>Models</term><term>Monkey</term><term>Nervous system diseases</term><term>Parkinson disease</term><term>Primates</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Syndrome extrapyramidal</term><term>Maladie de Parkinson</term><term>Pathologie du système nerveux</term><term>Récepteur biologique</term><term>Primates</term><term>Modèle</term><term>Animal</term><term>Singe</term><term>Adénosine</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Singe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D<sub>2</sub> receptors by antipsychotics, respectively. Adenosine A<sub>2A</sub> receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D<sub>2</sub> receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A<sub>2A</sub> receptor activation contributes to the overdrive of the indirect pathway. A<sub>2A</sub> receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A<sub>2A</sub> receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A<sub>2A</sub> receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A<sub>2A</sub> receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Hodgson, Robert A" sort="Hodgson, Robert A" uniqKey="Hodgson R" first="Robert A." last="Hodgson">Robert A. Hodgson</name></noRegion><name sortKey="Grzelak, Michael E" sort="Grzelak, Michael E" uniqKey="Grzelak M" first="Michael E." last="Grzelak">Michael E. Grzelak</name><name sortKey="Hunter, John C" sort="Hunter, John C" uniqKey="Hunter J" first="John C." last="Hunter">John C. Hunter</name><name sortKey="Kazdoba, Tatiana M" sort="Kazdoba, Tatiana M" uniqKey="Kazdoba T" first="Tatiana M." last="Kazdoba">Tatiana M. Kazdoba</name><name sortKey="Neustadt, Bernard R" sort="Neustadt, Bernard R" uniqKey="Neustadt B" first="Bernard R." last="Neustadt">Bernard R. Neustadt</name><name sortKey="Pond, Annamarie J" sort="Pond, Annamarie J" uniqKey="Pond A" first="Annamarie J." last="Pond">Annamarie J. Pond</name><name sortKey="Stamford, Andrew W" sort="Stamford, Andrew W" uniqKey="Stamford A" first="Andrew W." last="Stamford">Andrew W. Stamford</name><name sortKey="Varty, Geoffrey B" sort="Varty, Geoffrey B" uniqKey="Varty G" first="Geoffrey B." last="Varty">Geoffrey B. Varty</name></country><country name="Canada"><noRegion><name sortKey="Bedard, Paul J" sort="Bedard, Paul J" uniqKey="Bedard P" first="Paul J." last="Bedard">Paul J. Bedard</name></noRegion><name sortKey="Belanger, Nancy" sort="Belanger, Nancy" uniqKey="Belanger N" first="Nancy" last="Belanger">Nancy Belanger</name><name sortKey="Dare, Aurelie" sort="Dare, Aurelie" uniqKey="Dare A" first="Aurelie" last="Dare">Aurelie Dare</name><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Therese" last="Di Paolo">Therese Di Paolo</name><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Gregoire">Laurent Gregoire</name><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Gregoire">Laurent Gregoire</name><name sortKey="Hadjtahar, Abdallah" sort="Hadjtahar, Abdallah" uniqKey="Hadjtahar A" first="Abdallah" last="Hadjtahar">Abdallah Hadjtahar</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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