A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease
Identifieur interne : 002B51 ( Main/Exploration ); précédent : 002B50; suivant : 002B52A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease
Auteurs : Tom H. Johnston [Canada] ; Joohyung Lee [Canada] ; Jordi Gomez-Ramirez [Canada] ; Susan H. Fox [Canada] ; Jonathan M. Brotchie [Canada]Source :
- Experimental neurology : (Print) [ 0014-4886 ] ; 2005.
Descripteurs français
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
- Action potential, Adrenergic Uptake Inhibitors (pharmacology), Adrenergic alpha-Antagonists (therapeutic use), Amantadine, Amantadine (therapeutic use), Animal, Animal model, Animals, Anti-Dyskinesia Agents (therapeutic use), Antiparkinson Agents (adverse effects), Antiparkinson Agents (therapeutic use), Complication, Dizocilpine Maleate (therapeutic use), Dopamine Agents (therapeutic use), Dose-Response Relationship, Drug, Drug Evaluation, Preclinical (methods), Dyskinesia, Dyskinesia, Drug-Induced (drug therapy), Excitatory Amino Acid Antagonists (therapeutic use), Haloperidol, Haloperidol (therapeutic use), Human, Idazoxan, Idazoxan (therapeutic use), Levodopa, Levodopa (adverse effects), Levodopa (therapeutic use), Male, Medical screening, Monkey, Motor Activity (drug effects), NMDA, Parkinson Disease (drug therapy), Parkinson disease, Primates, Rat, Rats, Rats, Sprague-Dawley, Reserpine, Reserpine (pharmacology), Rodentia, Toxicity, Treatment.
- MESH :
- chemical , adverse effects : Antiparkinson Agents, Levodopa.
- chemical , pharmacology : Adrenergic Uptake Inhibitors, Reserpine.
- chemical , therapeutic use : Adrenergic alpha-Antagonists, Amantadine, Anti-Dyskinesia Agents, Antiparkinson Agents, Dizocilpine Maleate, Dopamine Agents, Excitatory Amino Acid Antagonists, Haloperidol, Idazoxan, Levodopa.
- drug effects : Motor Activity.
- drug therapy : Dyskinesia, Drug-Induced, Parkinson Disease.
- methods : Drug Evaluation, Preclinical.
- Animals, Dose-Response Relationship, Drug, Male, Rats, Rats, Sprague-Dawley.
Abstract
L-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate L-DOPA-induced behaviours in the reserpine-treated rat. Administration of L-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of L-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with L-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of L-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in L-DOPA-induced vertical activity in the reserpine-treated rat.
Affiliations:
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Johnston</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Joohyung" sort="Lee, Joohyung" uniqKey="Lee J" first="Joohyung" last="Lee">Joohyung Lee</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Gomez Ramirez, Jordi" sort="Gomez Ramirez, Jordi" uniqKey="Gomez Ramirez J" first="Jordi" last="Gomez-Ramirez">Jordi Gomez-Ramirez</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Toronto Western Research Institute, Toronto Western Hospital, University Health Network</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Movement Disorders Clinic, Toronto Western Hospital, and Division of Neurology, University of Toronto</s1><s2>Ontario</s2><s3>CAN</s3><sZ>4 aut.</sZ></inist:fA14><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName><orgName type="university">Université de Toronto</orgName></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Atuka Ltd., One Dundas St. West, Suite 2500, West</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>5 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario</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="2005">2005</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>Action potential</term><term>Adrenergic Uptake Inhibitors (pharmacology)</term><term>Adrenergic alpha-Antagonists (therapeutic use)</term><term>Amantadine</term><term>Amantadine (therapeutic use)</term><term>Animal</term><term>Animal model</term><term>Animals</term><term>Anti-Dyskinesia Agents (therapeutic use)</term><term>Antiparkinson Agents (adverse effects)</term><term>Antiparkinson Agents (therapeutic use)</term><term>Complication</term><term>Dizocilpine Maleate (therapeutic use)</term><term>Dopamine Agents (therapeutic use)</term><term>Dose-Response Relationship, Drug</term><term>Drug Evaluation, Preclinical (methods)</term><term>Dyskinesia</term><term>Dyskinesia, Drug-Induced (drug therapy)</term><term>Excitatory Amino Acid Antagonists (therapeutic use)</term><term>Haloperidol</term><term>Haloperidol (therapeutic use)</term><term>Human</term><term>Idazoxan</term><term>Idazoxan (therapeutic use)</term><term>Levodopa</term><term>Levodopa (adverse effects)</term><term>Levodopa (therapeutic use)</term><term>Male</term><term>Medical screening</term><term>Monkey</term><term>Motor Activity (drug effects)</term><term>NMDA</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson disease</term><term>Primates</term><term>Rat</term><term>Rats</term><term>Rats, Sprague-Dawley</term><term>Reserpine</term><term>Reserpine (pharmacology)</term><term>Rodentia</term><term>Toxicity</term><term>Treatment</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Antiparkinson Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adrenergic Uptake Inhibitors</term><term>Reserpine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Adrenergic alpha-Antagonists</term><term>Amantadine</term><term>Anti-Dyskinesia Agents</term><term>Antiparkinson Agents</term><term>Dizocilpine Maleate</term><term>Dopamine Agents</term><term>Excitatory Amino Acid Antagonists</term><term>Haloperidol</term><term>Idazoxan</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Drug Evaluation, Preclinical</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Dose-Response Relationship, Drug</term><term>Male</term><term>Rats</term><term>Rats, Sprague-Dawley</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dyskinésie</term><term>Parkinson maladie</term><term>Rodentia</term><term>Animal</term><term>Lévodopa</term><term>Complication</term><term>Traitement</term><term>Primates</term><term>Modèle animal</term><term>Dépistage</term><term>Toxicité</term><term>Homme</term><term>Singe</term><term>Réserpine</term><term>Rat</term><term>Amantadine</term><term>Idazoxan</term><term>Halopéridol</term><term>NMDA</term><term>Potentiel action</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term><term>Singe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">L-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate L-DOPA-induced behaviours in the reserpine-treated rat. Administration of L-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of L-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with L-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of L-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in L-DOPA-induced vertical activity in the reserpine-treated rat.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><name sortKey="Gomez Ramirez, Jordi" sort="Gomez Ramirez, Jordi" uniqKey="Gomez Ramirez J" first="Jordi" last="Gomez-Ramirez">Jordi Gomez-Ramirez</name><name sortKey="Lee, Joohyung" sort="Lee, Joohyung" uniqKey="Lee J" first="Joohyung" last="Lee">Joohyung Lee</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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