R-DEPRENYL AND R-2-HEPTYL-N-METHYLPROPARGYLAMINE PREVENT APOPTOSIS INCEREBELLAR GRANULE NEURONS INDUCED BY CYTOSINE-ARABINOSIDE BUT NOT LOW EXTRACELLULAR POTASSIUM

R-Deprenyl and R-2-heptyl-N-methylpropargylamine (R-2-HMP) are compoun ds that have been shown to reduce neuronal death in various in vitro a nd in vivo models involving apoptosis but do not always prevent apopto sis, In the present study we have examined the effects of these compou nds and their S enantiomers on cytosine arabinoside (ara C)-induced ap optosis and low K+-induced apoptosis in cerebellar granule cells in pr imary culture. It was found that R-deprenyl and R-2-HMP could prevent ara C-induced apoptosis with an EC50 around 10(-9) M but could not pre vent low K+-induced apoptosis. S-Deprenyl and S-2-HMP did not prevent apoptosis under any conditions but were found to antagonize the antiap optotic actions of R-deprenyl and R-2-HMP. Using the fluorescent mitoc hondrial dye chloromethyltetramethylrhodamine methyl ester it was foun d that there was a loss of mitochondrial function in cerebellar granul e cells exposed to ara C but not low K+ medium. R-Deprenyl and R-2-HMP prevented the ara C-induced loss of mitochondrial function. It is con cluded that R-deprenyl and R-2-HMP prevent apoptosis of cerebellar gra nule cells by a mechanism that is independent of monoamine oxidase inh ibition and that they act on the same site to prevent specifically apo ptosis involving a loss of mitochondrial membrane potential, possibly p53-dependent apoptosis.