(-)-DEPRENYL REDUCES NEURONAL APOPTOSIS AND FACILITATES NEURONAL OUTGROWTH BY ALTERING PROTEIN-SYNTHESIS WITHOUT INHIBITING MONOAMINE-OXIDASE

(-)-Deprenyl stereospecifically reduces neuronal death even after neur ons have sustained seemingly lethal damage at concentrations too small to cause monoamine oxidase-B (MAO-B) inhibition. (-)-Deprenyl can als o influence the process growth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cel ls at concentrations too small to inhibit MAO. In accord with the earl ier work of others, we showed that (-)-deprenyl alters the expression of a number mRNAs or proteins in nerve and glial cells and that the al terations in gene expression/protein synthesis are the result of a sel ective action on transcription. The alterations in gene expression/pro tein synthesis are accompanied by a decrease in DNA fragmentation char acteristic of apoptosis and the death of responsive cells. The once-pr oteins Bcl-2 and Bar and the scavenger proteins Cu/Zn superoxide dismu tase (SOD1) and Mn superoxide dismutase (SOD2) are among the 40-50 pro teins whose synthesis is altered by (-)-deprenyl. Since mitochondrial ATP production depends on mitochondrial membrane potential (MMP) and m itochondrial failure has been shown to be one of the earliest events i n apoptosis, we used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl are accompanied by a maintenance of mitochondrial membrane potential, a de crease in intramitochondrial calcium and a decrease in cytoplasmic oxi dative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and to decrease cyt oplasmic oxidative radical levels and thereby to reduce apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may contribute to the development of new therapi es for neurodegenerative diseases.