Rasagiline [N‐propargyl‐1R(+)‐aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

Abstract

1. Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(-) enantiomer is relatively inactive in the tissues examined. 3. The in vitro IC(50) values for inhibition of rat brain MAO activity by rasagiline are 4.43+/-0.92 nM (type B), and 412+/-123 nM (type A). The ED(50) values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1+/-0.01, 0.042+/-0.0045 mg kg(-1) respectively for MAO-B, and 6.48+/-0.81, 2.38+/-0.35 mg kg(-1) respectively for MAO-A. 4. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED(50) values of 0.014+/-0.002 and 0.013+/-0.001 mg kg(-1) respectively. 5. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.

Neuroprotective effects of selegiline on rat neural stem cells treated with hydrogen peroxide

“…In vitro and in vivo experiments have demonstrated that selegiline is a potent inhibitor of MAO-B and also enhances the synthesis of neurotrophic factors including glial cell-derived neurotrophic factor and brain-derived neurotrophic factor (9,27,28). As a selective MAO-B inhibitor, selegiline may be used as an anti-PD drug to exert antioxidant and anti-apoptotic effects (29,30).…”

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

“…It has neuroprotective and anti‐apoptotic properties in a variety of in vitro and in vivo animal models relevant to Parkinson's disease 8, 9, 10, 11. RG can rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by the mitochondria permeability transition pore 12.…”

Mitochondrial proteomics as a selective tool for unraveling Parkinson’s disease pathogenesis

“…Such drugs include N-propargyl-1R-aminoindan (rasagiline) and l-deprenyl (selegiline), which act as potent inhibitors of MAO-B [123], the major enzymatic step in the brain for converting DA to its inactive catabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA). Inhibition of MAO-B retards the otherwise rapid turnover of striatal DA.…”