Noradrenoceptor antagonism with idazoxan improves L-dopa-induced dyskinesias in MPTP monkeys.
Treatment of Parkinson's disease with L-dopa is plagued in a majority of patients by dyskinesias. Noradrenaline/dopamine interactions are proposed on behavioral, biochemical, physiological and anatomical grounds. The aim of the study was to test the potential antidyskinetic effect of the alpha2-adrenoceptor antagonist, idazoxan, in a primate model of Parkinson's disease. Six female cynomolgus monkeys previously rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and presenting an unchanged syndrome for several months were used. All responded readily to L-dopa but had developed dyskinesias which were manifested with each dose. In the first part of the study, seven doses of idazoxan (ranging from 0.25 mg/kg to 10 mg/kg, p.o.) were administered together with the vehicle or in combination with a fixed dose of L-dopa/benserazide (100/25 mg, p.o.). In the second part of the study, a fixed dose of idazoxan (7.5 mg/kg) was administered daily for 10 days and L-dopa was added to idazoxan on days 1, 4, 7 and 10. Vehicle (empty capsule) was used as control. Idazoxan, by itself (ranging from 5 mg/kg to 10 mg/kg), increased locomotor activity and improved the disability score with virtually no dyskinesias in three animals. In combination with L-dopa, idazoxan did not impair the antiparkinsonian response but significantly reduced dyskinesias in all six animals up to 65% at doses of 7.5 mg/kg and 10 mg/kg and delayed their onset, so that the "ON" state without dyskinesias was prolonged. The antidyskinetic effect of idazoxan was maintained when repeatedly administered for 10 days. On day 10, the locomotor response to L-dopa was significantly potentiated by chronic administration of idazoxan. Our results indicate that idazoxan has some antiparkinsonian effect of its own and may constitute a useful adjunct to L-dopa as it can reduce dyskinesias without impairing the relief of symptoms, this effect being maintained over time in this model.
Grondin
R
R
Department of Medicine, Faculty of Medicine, Laval University Research Center, Ste-Foy, Québec, Canada.
Hadj Tahar
A
A
Doan
V D
VD
Ladure
P
P
Bédard
P J
PJ
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D019329:Idazoxan / Q000627:therapeutic use*; D007980:Levodopa / Q000633:toxicity*; D020267:MPTP Poisoning / Q000188:drug therapy; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000502:physiology; D010300:Parkinson Disease / Q000188:drug therapy*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D009638:Norepinephrine; D019329:Idazoxan