Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline

A potent inhibitor of type B monoamine oxidase, (-)deprenyl, is known to pr otect or rescue dying neurons, independent of inhibition of the enzyme acti vity. After long term administration to rodents, a propargylamine structura lly related to (-)deprenyl, (R)(+)-N-propargyl-1-aminoindan (rasagiline) in creased the activities of anti-oxidative enzymes, superoxide dismutase and catalase. Rasagiline protected in vitro dopamine cells from apoptosis induc ed by oxidative stress or neurotoxins. The mechanism of the anti-apoptotic effect was studied by in vitro experiments using human dopaminergic neurobl astoma, SH-SY5Y cells. Peroxynitrite-generating N-morpholino sydonimine (SI N-1) induced apoptosis in SH-SY5Y cells via disruption of mitochondrial mem brane potential (Delta psi m), followed by caspase 3 activation. Rasagiline prevented the loss of Delta psi m, the initial step to apoptosis, and also following caspase 3-activation and DNA fragmentation. The results suggest that rasagiline may interact with the specific molecule in the mitochondria and suppress the death signal transduction. By the anti-apoptotic function , rasagiline may rescue or protect declining neurons in aging and neurodege nerative disorders, such as Parkinson's disease. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.