INHIBITION OF GLUTATHIONE SYNTHESIS CAN ENHANCE CYCLOHEXIMIDE-INDUCEDPROTECTION OF DEVELOPING NEURONS AGAINST AXOTOMY

Developing neurons depend for survival on target-derived trophic subst ances. These are thought to block the expression of a genetic program of cell death. Nevertheless, it is known that less orderly events such as oxidative stress are involved in neuron death. In vivo, retinal ga nglion cell death induced by axotomy can be reduced by antioxidants. I n this study, we investigated the effects of inhibiting glutathione sy nthesis by means of buthionine sulfoximine to characterize the influen ce of endogenous glutathione-dependent antioxidant systems on ganglion cell death. Moreover, since protein synthesis inhibition by cyclohexi mide has been shown to enhance glutathione synthesis in vitro, we stud ied the effects on cell death of intraocular injections of buthionine sulfoximine, cycloheximide and combinations of the two inhibitors. Cyc loheximide's protective action did not seem to involve an increase in glutathione synthesis. Surprisingly, buthionine sulfoximine injected b efore cycloheximide enhanced its protective effects, whereas it inhibi ted them when injected later. We interpret our results as an interacti on between death-promoting effects of glutathione depletion through an elevation of free radical concentrations and cycloheximide-sensitive effects of oxidative stress through the synthesis of both death-inhibi ting and death-promoting proteins. (C) 1997 Elsevier Science B.V.