Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells

Abstract

Selegiline and rasagiline are selective and irreversible monoamine oxidase-B inhibitors that exert neuroprotective effects in various preclinical models. The aim of the present study was to examine the effect of selegiline and its major metabolite, l-methamphetamine in comparison to rasagiline and its major metabolite, 1- R-aminoindan on oxygen–glucose deprivation induced cell death in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. Our results show that selegiline reduces oxygen–glucose deprivation induced cell death by 30%. When the cultures were treated with rasagiline at similar concentrations, cell death induced by oxygen–glucose deprivation was reduced by 45–55%. l-methamphetamine, a major selegiline metabolite, but not 1- R-aminoindan, the major rasagiline metabolite, enhanced oxygen–glucose deprivation-induced cell death by 70%. Under normoxic conditions, both metabolites lack neurotoxicity. Concomitant exposure of the cultures under oxygen–glucose deprivation, to a combination of either selegiline and l-methamphetamine or rasagiline and 1- R-aminoindan, indicated that l-methamphetamine, but not 1- R-aminoindan, blocked the neuroprotective effect of the parental drug. These results suggest there may be a neuroprotective advantage of rasagiline over selegiline.