Rasagiline, a novel monoamine oxidase-B inhibitor with neuroprotective effects under ischemic conditions in PC12 cells

Rasagiline (N-propargyl-1R-aminoindan) is a novel, potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B), currently in Phase III trials for the treatment of Parkinson disease (PD). Rasagiline was shown to have neuroprotective properties in various in vitro and in vivo models independently of MAO-B inhibition. Recently, we developed an in vitro oxygen-glucose deprivation (OGD) model of time-course dependent neuronal cell death in nerve growth factor (NGF)-differentiated PC12 cultures. OGD was accompanied by activation of the arachidonic acid cascade and a decrease in ATP content, changes typical of ischemic conditions. OGD for 3 h followed by reoxygenation for 18 h caused about 30-40% cell death. These conditions are suitable for testing the effect of potential neuroprotective compounds on neuronal cell death. Rasagiline markedly reduced OGD-induced cell death independently of MAO-B inhibition, reducing OGD-induced cell death even when added after the OGD insult. The compound also inhibited OGD-induced prostaglandin E₂ (PGE₂) release in a dose-dependent manner. At present, selegiline remains the only drug approved for PD therapy based on MAO-B inhibition. However, in contrast to selegiline, rasagiline is not metabolized to amphetamine-like products, which cause adverse side effects and neuronal cell death. Therefore, rasagiline, whose neuroprotective properties are uncomplicated by the production of neurotoxic metabolites, may have an advantage over selegiline in the treatment of PD. (C) 2000 Wiley-Liss, Inc.