The alpha2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease.
Dopamine replacement therapy in patients with Parkinson's disease is plagued by the emergence of abnormal involuntary movements known as L-dopa-induced dyskinesias. It has been demonstrated that yohimbine can reduce L-dopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Yohimbine is, among other things, an alpha-adrenergic receptor antagonist. In this study, we demonstrate that the selective and potent alpha2-adrenergic receptor antagonist idazoxan reduces L-dopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease. The alpha2-adrenergic receptor antagonists rauwolscine and yohimbine also reduce L-dopa-induced dyskinesia. Furthermore, we demonstrate that coadministration of idazoxan with L-dopa can provide an anti-parkinsonian action more than twice the length of that seen with L-dopa alone. However, idazoxan as a monotherapy displayed no anti-parkinsonian actions. We propose that idazoxan in combination with L-dopa may provide a novel approach to the treatment of Parkinson's disease that will not only reduce the dyskinetic side effects, but extend the anti-parkinsonian actions of L-dopa. Idazoxan, as an adjunct to dopamine replacement, may prove useful in the treatment of parkinsonian patients at all stages of disease progression.
Henry
B
B
Organon Laboratories Limited, Department of Pharmacology, Lanarkshire, Scotland, UK.
Fox
S H
SH
Peggs
D
D
Crossman
A R
AR
Brotchie
J M
JM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D018674:Adrenergic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002144:Callithrix; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020820:Dyskinesias / Q000188:drug therapy*; D005260:Female; D019329:Idazoxan / Q000494:pharmacology* / Q000627:therapeutic use*; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology / Q000627:therapeutic use
D018674:Adrenergic Antagonists; D000978:Antiparkinson Agents; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019329:Idazoxan