N-acetylcysteine (D- and L-stereoisomers) prevents apoptotic death of neuronal cells

In the present study we tested whether N-acetyl-L-cysteine (LNAC) affects apoptotic death of neuronal cells caused by trophic factor deprivation. LNAC, an antioxidant, elevates intracellular levels of glutathione. We used serum-deprived PC12 cells, neuronally differentiated PC12 cells deprived of serum and NGF, and NGF-deprived neonatal sympathetic neurons. In each case LNAC prevents apoptotic DNA fragmentation and maintains long-term survival in the absence of other trophic support. Unlike NGF, LNAC does not induce or maintain neurite outgrowth or somatic hypertrophy. To rule out actions of LNAC metabolic derivatives, we assessed N-acetyl-D-cysteine (DNAC). DNAC also prevents death of PC12 cells and sympathetic neurons. However, other antioxidants were ineffective in this regard. Since it has been hypothesized that trophic factors prevent neuronal death by either preventing or coordinating cell cycle progression, we tested whether LNAC or DNAC treatment can affect cell cycle. We found that both (but not other antioxidants) suppress proliferation and DNA synthesis by PC12 cells and do so at concentrations similar to those at which they prevent apoptotic death. Although the abilities of LNAC and DNAC to rescue cells from apoptosis triggered by trophic factor deprivation could derive from their direct influences on cellular responsiveness to oxidative stress, our observations raise the possibility of a mechanism involving cell cycle regulation.