Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats.
Identifieur interne : 000430 ( Ncbi/Checkpoint ); précédent : 000429; suivant : 000431Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats.
Auteurs : Roberto Coccurello [France] ; Nathalie Breysse ; Marianne AmalricSource :
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [ 0893-133X ] ; 2004.
English descriptors
- KwdEn :
- Adenosine A2 Receptor Antagonists, Animals, Brain (pathology), Caffeine (pharmacology), Conditioning, Operant (drug effects), Dopamine (physiology), Dopamine and cAMP-Regulated Phosphoprotein 32, Gene Expression Regulation (drug effects), Genes, fos, Male, Nerve Tissue Proteins (metabolism), Oxidopamine, Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (drug therapy), Parkinson Disease, Secondary (pathology), Phosphoproteins (metabolism), Phosphorylation, Psychomotor Performance (drug effects), Pyridines (pharmacology), Rats, Reaction Time (drug effects), 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 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.
DOI: 10.1038/sj.npp.1300444
PubMed: 15039773
Affiliations:
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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><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2004">2004</date><idno type="RBID">pubmed:15039773</idno><idno type="pmid">15039773</idno><idno type="doi">10.1038/sj.npp.1300444</idno><idno type="wicri:Area/PubMed/Corpus">001007</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001007</idno><idno type="wicri:Area/PubMed/Curation">000F66</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000F66</idno><idno type="wicri:Area/PubMed/Checkpoint">000F66</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000F66</idno><idno type="wicri:Area/Ncbi/Merge">000430</idno><idno 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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></series></biblStruct></sourceDesc></fileDesc><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></keywords></textClass></profileDesc></teiHeader><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></TEI><affiliations><list><country><li>France</li></country><region><li>Provence-Alpes-Côte d'Azur</li></region><settlement><li>Marseille</li></settlement><orgName><li>Université de Provence</li></orgName></list><tree><noCountry><name sortKey="Amalric, Marianne" sort="Amalric, Marianne" uniqKey="Amalric M" first="Marianne" last="Amalric">Marianne Amalric</name><name sortKey="Breysse, Nathalie" sort="Breysse, Nathalie" uniqKey="Breysse N" first="Nathalie" last="Breysse">Nathalie Breysse</name></noCountry><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Coccurello, Roberto" sort="Coccurello, Roberto" uniqKey="Coccurello R" first="Roberto" last="Coccurello">Roberto Coccurello</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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