COOPERATION BETWEEN GLUTATHIONE DEPLETION AND PROTEIN-SYNTHESIS INHIBITION AGAINST NATURALLY-OCCURRING NEURONAL DEATH

It is generally agreed that naturally-occurring neuronal death in deve loping animals is dependent on the synthesis of proteins. Oxidative st ress, as when intracellular concentrations of free radicals are raised or when cell constituents such as membrane lipids or protein thiols a re oxidized, is also involved in various types of neuronal death. In t he present report, we show that the number of naturally dying retinal cells in the chick embryo can be reduced by intraocular injections of cycloheximide, an inhibitor of protein synthesis. L-buthionine-[S,R]-s ulfoximine, an inhibitor of glutathione synthesis, can either enhance or diminish the cell death, depending on the conditions of treatment. Moreover, when the two inhibitors are combined, L-buthionine-[S.R]-sul foximine potentiates the neuroprotective effects of cycloheximide. Mea surements of retinal glutathione concentration and protein synthesis s how the specificity of the treatments: buthionine-sulfoximine diminish es glutathione concentrations but not protein synthesis whereas cycloh eximide inhibits protein synthesis without decreasing glutathione conc entrations. Naturally-occurring neuronal death thus seems to involve t he synthesis of proteins, and is also influenced by oxidative phenomen a. Our results extend previous data in tectal-lesioned embryos, and su ggest that a moderate, non-lethal oxidative stress can enhance the res istance of ganglion cells that might otherwise have died (spontaneousl y or following axotomy) owing to insufficient retrograde trophic suppo rt. (C) 1998 IBRO. Published by Elsevier Science Ltd.