An appraisal of the antiparkinsonian activity of piribedil in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets.
The D2 dopamine agonist piribedil is not widely used in the treatment of Parkinson's disease because it was thought to be effective mainly on parkinsonian tremor and to produce a high incidence of peripheral side effects, particular nausea. In this study, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates to reevaluate the antiparkinsonian ability of piribedil after its oral administration in the presence or absence of domperidone pretreatment. Adult common marmosets (Callithrix jacchus) were treated with the nigral toxin MPTP to induce a parkinsonian syndrome characterised primarily by bradykinesia and other motor deficits. Oral administration of a solution of piribedil [1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine] produced a dose-related reversal of all MPTP locomotor and behavioural deficits. However, this effect was short lived and associated with unwanted effects, particular nausea and retching, which clearly hindered locomotion. In contrast, after pretreatment with the peripheral dopamine antagonist domperidone, administration of piribedil did not induce nausea or retching in MPTP-treated marmosets. In these animals, piribedil caused a more marked and longer lasting enhancement of locomotor activity and a further reduction in behavioural deficits than that observed after administration of piribedil alone. In addition, piribedil induced increased vigilance and awareness. These data show that piribedil can reverse akinesia and rigidity in MPTP-treated primates. In addition, they show the drug to be effective without peripheral side effects when used in conjunction with domperidone. These data indicate that piribedil should be an effective monotherapy for Parkinson's disease.
Smith
L
L
Neurodegenerative Diseases Research Centre, King's College, London, England, UK.
De Salvia
M
M
Jenner
P
P
Marsden
C D
CD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000633:toxicity*; D002144:Callithrix; D004294:Domperidone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D010891:Piribedil / Q000008:administration & dosage / Q000633:toxicity*; D011292:Premedication; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
D000932:Antiemetics; D000978:Antiparkinson Agents; D017448:Receptors, Dopamine D2; D004294:Domperidone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010891:Piribedil