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 i rreversibie inhibitor of monoamine oxidase B (MAO-B), currently in Phase ii i trials for the treatment of Parkinson disease (PD). Rasagiline was shown to have neuroprotective properties in various in vitro and in vivo models i ndependently of MAO-B inhibition. Recently, we developed an in vitro oxygen -glucose deprivation (OGD) model of time-course dependent neuronal cell dea th in nerve growth factor (NGF)-differentiated PC12 cultures. OGD was accom panied by activation of the arachidonic acid cascade and a decrease in ATP content, changes typical of ischemic conditions. OGD for 3 h followed by re oxygenation for 18 h caused about 30-40% cell death. These conditions are s uitable for testing the effect of potential neuroprotective compounds on ne uronal cell death. Rasagiline markedly reduced OGD-induced cell death indep endently of MAO-B inhibition, reducing OGD-induced cell death even when add ed after the OGD insult. The compound also inhibited OGD-induced prostaglan din E-2 (PGE(2)) release in a dose-dependent manner. At present, selegiline remains the only drug approved for PD therapy based on MAO-B inhibition. H owever, in contrast to selegiline, rasagiline is not metabolized to ampheta mine-like products, which cause adverse side effects and neuronal cell deat h. Therefore, rasagiline, whose neuroprotective properties are uncomplicate d by the production of neurotoxic metabolites, may have an advantage over s elegiline in the treatment of PD. Drug Dev. Res. 50:285-290, 2000. (C) 2000 Wiley-Liss, Inc.