Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours.
Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.
Finberg
John P M
JP
Pharmacology Department, Rappaport Family Faculty of Medicine, Technion, POB 9649, Haifa, Israel. finberg@techunix.technion.ac.il
Youdim
Moussa B H
MB
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001679:Biogenic Amines / Q000378:metabolism; D001763:Blepharoptosis / Q000139:chemically induced / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000633:toxicity; D012701:Serotonin / Q000378:metabolism*
D000978:Antiparkinson Agents; D001679:Biogenic Amines; D007189:Indans; C031967:rasagiline; D012701:Serotonin; D012110:Reserpine; D004298:Dopamine