Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders.
N-propargyl-1-(R)aminoindan (rasagiline) is a new and selective irreversible MAO-B inhibitor, currently being considered as the mesylate salt for potential therapy in certain neurological disorders. It has been studied in animal models of cognition and motor dysfunction. Its ability to restore normal motor activity was determined in models of acute drug-induced dopaminergic dysfunction: Its effects in improving cognition and memory deficits was studied in adult and senescent rats that had been exposed to prolonged hypoxia, then subjected to the passive and active avoidance tests. In alpha-methyl-p-tyrosine (alpha-MpT)-induced hypokinesia (100-120 mg/kg, i.p.) pretreatment with rasagiline at 2.5 mg/kg i.p. restored motor activity to control level. But pretreatment with reserpine abolished the protective effect of rasagiline. Rasagiline at 0.5 mg/kg/day was protective against alpha-MpT also in hypoxia-lesioned rats. In haloperidol-induced catalepsy in rats (1.5 mg/kg, s.c.) or mice (4-6 mg/kg s.c.), rasagiline improved recovery of normal locomotion, gait and coordination at 0.4-2.4 mg/kg i.p. and 1.8-1.5 mg/kg i.p., respectively. In amphetamine-induced stereotypy (0.6 mg/kg s.c., rasagiline potentiated this effect at 1.5 mg/kg i.p. In hypoxia-induced impairment of memory and learning, rasagiline at 0.32-0.5 mg/kg/day per os improved performance of adult rats in passive and active avoidance, and of senescent rats in active avoidance. Selegiline was either ineffective or less effective at equivalent doses. Racemic N-propargyl-1-aminoindan (AGN-1135), besides being of lower potency, had a different dose-dependency than rasagiline in antagonizing haloperidol-induced catalepsy or alpha-MpT-induced hypokinesia. 1-(R)aminoindan ((R)AI), a metabolite of rasagiline, in relatively high doses produced effects that were distinct in certain respects from those of rasagiline.
Speiser
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Department of Physiology and Pharmacology, Tel Aviv University, Israel.
Levy
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Cohen
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D000375:Aging; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy*; D006220:Haloperidol / Q000633:toxicity; D018476:Hypokinesia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D019805:alpha-Methyltyrosine
D007189:Indans; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline; D019805:alpha-Methyltyrosine; D006220:Haloperidol