Rasagiline enhances L-DOPA-induced contralateral turning in the unilateral 6-hydroxydopamine-lesioned guinea-pig.
The modification of L-3,4-dihydrooxyphenylalanine- (L-DOPA-) induced turning response by the new selective monoamine oxidase type B (MAO-B) inhibitor rasagiline was studied in guinea-pigs bearing a unilateral 6-hydroxydopamine-induced lesion in the substantia nigra. In an initial experiment, it was established that contralateral turning is induced in lesioned guinea-pigs in response to apomorphine (18 mg/kg i.p.) and L-DOPA/carbidopa (15/3.5 mg/kg i.p.), while ipsilateral turning is induced by S(+)-methamphetamine (7 mg/kg i.p.). The effect of rasagiline was studied in a chronic treatment regimen, in which animals were treated with rasagiline (0.05 mg/kg s.c.) or saline s.c. daily commencing 2 weeks after lesioning, and L-DOPA/carbidopa (4:1 mg/kg) was administered once daily for 21 days. Only guinea-pigs with 95% or more depletion of striatal dopamine were included in this study. Guinea-pigs treated with rasagiline had a significantly increased intensity and duration of turning in response to L-DOPA (P <0.05 by repeated measures ANOVA) over the 21-day period. On day 21, turning averaged 806+/-105 (n=10) vs 442+/-123 (n=11) turns per 180 min for rasagiline and vehicle treated animals, respectively (P <0.05); turning duration half-time averaged 81+/-15.4 (n=10) as opposed to 33+/-7.6 (n=11) min for rasagiline and vehicle treatments (P <0.01). Concentration of dopamine in intact striatum was significantly increased (69.3+/-2.1 and 60.3+/-2.4 pmol/mg tissue for rasagiline and vehicle, P <0.05) and levels of dihydroxyphenylacetic acid and homovanillic acid were decreased by the rasagiline treatment. Activity of brain MAO-B was 8.6+/-2.9% and MAO-A was 71+/-1.5% that of control in rasagiline-treated animals. Chronic, selective inhibition of MAO-B by rasagiline potentiated L-DOPA-induced turning in this rodent model.
Moses
David
D
Pharmacology Department, Rappaport Family Faculty of Medicine, Technion, P.O. Box 9649, 31096 Haifa, Israel.
Gross
Aviva
A
Finberg
John P M
JP
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D007839:Functional Laterality; D006168:Guinea Pigs; D006719:Homovanillic Acid / Q000494:pharmacology; D007189:Indans; D008297:Male; D008959:Models, Neurological; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D015203:Reproducibility of Results; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C031967:rasagiline; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D004298:Dopamine; D006719:Homovanillic Acid