Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats
Identifieur interne : 002F90 ( Main/Curation ); précédent : 002F89; suivant : 002F91Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats
Auteurs : Roberto Coccurello [France] ; Nathalie Breysse [France] ; Marianne Amalric [France]Source :
- Neuropsychopharmacology : (New York, NY) [ 0893-133X ] ; 2004.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
- A2A adenosine receptor, Adenosine A2 Receptor Antagonists, Animal, Animals, Antagonist, Antiparkinson agent, Brain (pathology), Caffeine (pharmacology), Conditioning, Operant (drug effects), Dopamine (physiology), Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation (drug effects), Genes, fos, Glutamate receptor, Male, Mechanism of action, Metabotropic receptor, Nerve Tissue Proteins (metabolism), Oxidopamine, Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (drug therapy), Parkinson Disease, Secondary (pathology), Parkinson disease, Phosphoproteins (metabolism), Phosphorylation, Psychomotor Performance (drug effects), Pyridines (pharmacology), Rat, Rats, Reaction Time (drug effects), Reaction time, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate (antagonists & inhibitors), Sympatholytics.
- MESH :
- chemical , antagonists & inhibitors : Receptors, Metabotropic Glutamate.
- chemical , metabolism : Nerve Tissue Proteins, Phosphoproteins.
- chemical , pharmacology : Caffeine, Pyridines.
- chemical , physiology : Dopamine.
- chemical : Adenosine A2 Receptor Antagonists, Dopamine and cAMP-Regulated Phosphoprotein 32, Oxidopamine, Receptor, Metabotropic Glutamate 5, Sympatholytics.
- chemically induced : Parkinson Disease, Secondary.
- drug effects : Conditioning, Operant, Gene Expression Regulation, Psychomotor Performance, Reaction Time.
- drug therapy : Parkinson Disease, Secondary.
- pathology : Brain, Parkinson Disease, Secondary.
- Animals, Genes, fos, Male, Phosphorylation, Rats.
Abstract
Recent evidence suggest that antagonism of adenosine A2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A and the glutamate subtype 5 metabotropic receptors (mGlu5) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A2A and mGlus receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A2A and mGlu5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.
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Pascal:04-0439077Le document en format XML
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<term>Animals</term>
<term>Antagonist</term>
<term>Antiparkinson agent</term>
<term>Brain (pathology)</term>
<term>Caffeine (pharmacology)</term>
<term>Conditioning, Operant (drug effects)</term>
<term>Dopamine (physiology)</term>
<term>Dopamine and cAMP-Regulated Phosphoprotein 32</term>
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<term>Mechanism of action</term>
<term>Metabotropic receptor</term>
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<term>Parkinson Disease, Secondary (chemically induced)</term>
<term>Parkinson Disease, Secondary (drug therapy)</term>
<term>Parkinson Disease, Secondary (pathology)</term>
<term>Parkinson disease</term>
<term>Phosphoproteins (metabolism)</term>
<term>Phosphorylation</term>
<term>Psychomotor Performance (drug effects)</term>
<term>Pyridines (pharmacology)</term>
<term>Rat</term>
<term>Rats</term>
<term>Reaction Time (drug effects)</term>
<term>Reaction time</term>
<term>Receptor, Metabotropic Glutamate 5</term>
<term>Receptors, Metabotropic Glutamate (antagonists & inhibitors)</term>
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<term>Psychomotor Performance</term>
<term>Reaction Time</term>
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<front><div type="abstract" xml:lang="en">Recent evidence suggest that antagonism of adenosine A<sub>2A</sub>
receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A<sub>2A</sub>
and the glutamate subtype 5 metabotropic receptors (mGlu<sub>5</sub>
) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A<sub>2A</sub>
and mGlus receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A<sub>2A</sub>
and mGlu<sub>5</sub>
receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.</div>
</front>
</TEI>
<double idat="0893-133X:2004:Coccurello R:simultaneous:blockade:of"><INIST><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Simultaneous blockade of adenosine A<sub>2A</sub>
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<author><name sortKey="Coccurello, Roberto" sort="Coccurello, Roberto" uniqKey="Coccurello R" first="Roberto" last="Coccurello">Roberto Coccurello</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A2A adenosine receptor</term>
<term>Animal</term>
<term>Antagonist</term>
<term>Antiparkinson agent</term>
<term>Glutamate receptor</term>
<term>Mechanism of action</term>
<term>Metabotropic receptor</term>
<term>Parkinson disease</term>
<term>Rat</term>
<term>Reaction time</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Parkinson maladie</term>
<term>Récepteur métabotropique</term>
<term>Récepteur glutamate</term>
<term>Animal</term>
<term>Rat</term>
<term>Temps réaction</term>
<term>Antagoniste</term>
<term>Récepteur adénosinique A2A</term>
<term>Antiparkinsonien</term>
<term>Mécanisme action</term>
</keywords>
</textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en">Recent evidence suggest that antagonism of adenosine A<sub>2A</sub>
receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A<sub>2A</sub>
and the glutamate subtype 5 metabotropic receptors (mGlu<sub>5</sub>
) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A<sub>2A</sub>
and mGlus receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A<sub>2A</sub>
and mGlu<sub>5</sub>
receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.</div>
</front>
</TEI>
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<PubMed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats.</title>
<author><name sortKey="Coccurello, Roberto" sort="Coccurello, Roberto" uniqKey="Coccurello R" first="Roberto" last="Coccurello">Roberto Coccurello</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex</wicri:regionArea>
<wicri:noRegion>Marseille cedex</wicri:noRegion>
<orgName type="university">Université de Provence</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Breysse, Nathalie" sort="Breysse, Nathalie" uniqKey="Breysse N" first="Nathalie" last="Breysse">Nathalie Breysse</name>
</author>
<author><name sortKey="Amalric, Marianne" sort="Amalric, Marianne" uniqKey="Amalric M" first="Marianne" last="Amalric">Marianne Amalric</name>
</author>
</titleStmt>
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<date when="2004">2004</date>
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<idno type="pmid">15039773</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats.</title>
<author><name sortKey="Coccurello, Roberto" sort="Coccurello, Roberto" uniqKey="Coccurello R" first="Roberto" last="Coccurello">Roberto Coccurello</name>
<affiliation wicri:level="4"><nlm:affiliation>Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Laboratoire de Neurobiologie de la Cognition, CNRS and Université de Provence, Marseille cedex</wicri:regionArea>
<wicri:noRegion>Marseille cedex</wicri:noRegion>
<orgName type="university">Université de Provence</orgName>
<placeName><settlement type="city">Marseille</settlement>
<region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Breysse, Nathalie" sort="Breysse, Nathalie" uniqKey="Breysse N" first="Nathalie" last="Breysse">Nathalie Breysse</name>
</author>
<author><name sortKey="Amalric, Marianne" sort="Amalric, Marianne" uniqKey="Amalric M" first="Marianne" last="Amalric">Marianne Amalric</name>
</author>
</analytic>
<series><title level="j">Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology</title>
<idno type="ISSN">0893-133X</idno>
<imprint><date when="2004" type="published">2004</date>
</imprint>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenosine A2 Receptor Antagonists</term>
<term>Animals</term>
<term>Brain (pathology)</term>
<term>Caffeine (pharmacology)</term>
<term>Conditioning, Operant (drug effects)</term>
<term>Dopamine (physiology)</term>
<term>Dopamine and cAMP-Regulated Phosphoprotein 32</term>
<term>Gene Expression Regulation (drug effects)</term>
<term>Genes, fos</term>
<term>Male</term>
<term>Nerve Tissue Proteins (metabolism)</term>
<term>Oxidopamine</term>
<term>Parkinson Disease, Secondary (chemically induced)</term>
<term>Parkinson Disease, Secondary (drug therapy)</term>
<term>Parkinson Disease, Secondary (pathology)</term>
<term>Phosphoproteins (metabolism)</term>
<term>Phosphorylation</term>
<term>Psychomotor Performance (drug effects)</term>
<term>Pyridines (pharmacology)</term>
<term>Rats</term>
<term>Reaction Time (drug effects)</term>
<term>Receptor, Metabotropic Glutamate 5</term>
<term>Receptors, Metabotropic Glutamate (antagonists & inhibitors)</term>
<term>Sympatholytics</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Receptors, Metabotropic Glutamate</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Nerve Tissue Proteins</term>
<term>Phosphoproteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Caffeine</term>
<term>Pyridines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Dopamine</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en"><term>Adenosine A2 Receptor Antagonists</term>
<term>Dopamine and cAMP-Regulated Phosphoprotein 32</term>
<term>Oxidopamine</term>
<term>Receptor, Metabotropic Glutamate 5</term>
<term>Sympatholytics</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>Conditioning, Operant</term>
<term>Gene Expression Regulation</term>
<term>Psychomotor Performance</term>
<term>Reaction Time</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease, Secondary</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Brain</term>
<term>Parkinson Disease, Secondary</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Genes, fos</term>
<term>Male</term>
<term>Phosphorylation</term>
<term>Rats</term>
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<front><div type="abstract" xml:lang="en">Recent evidence suggest that antagonism of adenosine A2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A2A and the glutamate subtype 5 metabotropic receptors (mGlu5) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A2A and mGlu5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A2A and mGlu5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.</div>
</front>
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