N-ACETYLCYSTEINE-PROMOTED SURVIVAL OF PC12 CELLS IS GLUTATHIONE-INDEPENDENT BUT TRANSCRIPTIONAL-DEPENDENT

Our prior work established that comparable concentrations of N-acetylc ysteine (NAG) both block the proliferation of PC12 cells and prevent d eath of trophic factor-deprived sympathetic neurons and PC12 cells. Th e present work addresses several aspects of the mechanisms of these ac tions, NAC increases intracellular levels of glutathione (GSH) by appr oximately 10-fold in PC12 cells, However, blockade of this increase by treatment with buthionine sulfoximine did not affect either promotion of survival or inhibition of DNA synthesis. Thus, these actions of NA C are independent of its effects on intracellular GSH, NAC's actions i n our system do not appear to be dependent on its anti-oxidant/radical scavenger properties, but may be due to its activity as a reductant, Consistent with this, several other reducing agents, the most effectiv e of which was 2,3-dimercaptopropanol, mimicked NAC in blocking DNA sy nthesis and suppressing death of PC12 cells and sympathetic neurons, F inally, we observed that in striking contrast to nerve growth factor a nd a number of other trophic agents, the survival-promoting effects of NAC on PC12 cells are blocked by actinomycin D. This suggests that NA C may act by inducing specific gene expression.