Anti-apoptotic function of propargylamine inhibitors of type-B monoamine oxidase

In Parkinson's disease and other neurodegenerative diseases, (-)deprenyl, an inhibitor of type B monoamine oxidase (MAO-B), has been proposed to protect or rescue declining neurons. However, clinical trials failed to confirm the neuroprotection, even though in vivo and in vitro studies suggested the possibilities. This paper describes the activities of propargylamine MAO-B inhibitors against apoptosis induced by an endogenous selective dopaminergic neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells. A series of propargylamines were shown to suppress the apoptotic cascade; preventing collapse of mitochondrial membrane potential, activation of caspase 3 and fragmentation of nucleosomal DNA. Among propargylamines, (R)-N-propargyl-1-aminoindan (rasagiline) was the most potent at preventing cell death. Rasagiline also prevented opening of permeability transition pore in insolated mitochondria. These results suggest that rasagiline and other propargylamines may regulate the apoptotic machinery in mitochondria and rescue or protect deteriorated neurons in neurodegenerative disorders.