MACROMOLECULAR-SYNTHESIS INHIBITORS PREVENT OXIDATIVE STRESS-INDUCED APOPTOSIS IN EMBRYONIC CORTICAL-NEURONS BY SHUNTING CYSTEINE FROM PROTEIN-SYNTHESIS TO GLUTATHIONE

Although macromolecular synthesis inhibitors have been demonstrated to prevent neuronal apoptosis in a number of paradigms, their mechanism of protection remains unclear. Recently, we found that neuronal death resulting from cystine deprivation, glutathione loss, and oxidative st ress is apoptotic and is prevented by inhibitors of macromolecular syn thesis. We now report that protection is associated with enhanced avai lability of acid-soluble cyst(e)ine and restoration of cellular glutat hione levels. N-acetylcysteine, an agent that delivers exogenous cyste ine intracellularly and raises glutathione, is also protective, while buthionine sulfoximine, an inhibitor of glutathione synthesis, prevent s protection by inhibitors of macromolecular synthesis. These results suggest that protection provided by these agents, in this paradigm, de rives from shunting of the amino acid cysteine from global protein syn thesis into the formation of the antioxidant glutathione.