Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders

Abstract

Summary. 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 a-methylp-tyrosine (a-MpT)-induced hypokinesia (100-120mg/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 a-MpT also in hypoxialesioned 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 normallocomotion, gait and coordination at 0.4-2.4mg/kg i.p. and 1.8-15mg/kg i.p., respectively. In amphetamine-induced stereotypy (0.6mg/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 haloperidolinduced catalepsy or a-MpT-induced hypokinesia. l-(R)aminoindan ((R)AI), a metabolite of rasagiline, in relatively high doses produced effects that were distinct in certain respects from those of rasagiline.

Double‐blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients

“…21,28 In addition, both rasagiline and its metabolite 1(R)-aminoindan protected against ␣-methyl-p-tyrosine-induced hypokinesia in rats previously exposed to hypoxia. 30 We conducted this double-blind, randomized, placebo-controlled trial as a pilot study to evaluate the safety and tolerability of orally administered rasagiline, and to make a preliminary assessment of its efficacy, when administered as once-daily monotherapy (1, 2, or 4 mg/ day) in patients with early PD and who were not receiving L-dopa. This trial was supported by Teva Pharmaceuticals.…”

Role of rasagiline in treating Parkinson’s disease: effect on disease progression

“…29 Rodent models have also demonstrated improvements in motor function after drug-induced dopaminergic dysfunction, and in motor and cognitive function post-hypoxia. 30 Furthermore, rasagiline-treated mice had faster recovery of motor function and spatial memory, and less cerebral edema, after closed head injury. Stroke models in the rat demonstrated decreased infarct sized after MCA occlusion and improved neurological severity scores in multiple models.…”

Neuroprotection by monoamine oxidase B inhibitors: a therapeutic strategy for Parkinson's disease?

“…(40) In contrast to selegiline, rasagiline is not metabolized to potentially toxic amphetaminic metabolites and its major metabolite, 1-R-aminoindan, has exhibited beneficial effects in animal models of PD. (50) Because of its selectivity towards MAO-B, rasagiline does not trigger the ''cheese effect'', (51) and was found to improve motor and cognitive function in PD animal models. (50) A recent clinical trial demonstrated the beneficial influence of rasagiline monotherapy in early stages of Parkinson's disease.…”

“…(50) Because of its selectivity towards MAO-B, rasagiline does not trigger the ''cheese effect'', (51) and was found to improve motor and cognitive function in PD animal models. (50) A recent clinical trial demonstrated the beneficial influence of rasagiline monotherapy in early stages of Parkinson's disease. (40) To evaluate the safety and efficacy of rasagiline, a multicenter clinical trial was carried out in which a total of 404 patients in early stages of PD were included.…”

“…The finding that propargylamines induce neuroprotection in neuronal cell cultures lacking MAO-B on the one hand, and the absence of any neuroprotective effect by clorgyline, a MAO-A inhibitor, on the other, also support the lack of correlation between neuroprotection and MAO inhibition. (57) Furthermore, the propargylamine concentration required for neuroprotection both in vitro and in vivo is 1 mM, whereas the IC 50 or Ki value for in vitro MAO-B inhibition is in the range of 6-30 nM. As shown in Tables 2 and 3, the major insults evoking neurotoxicity and, in many cases, leading to neuronal apoptosis, are depolarization, calcium overload and oxidative stress.…”