V. Castagne et Pgh. Clarke, INHIBITION OF GLUTATHIONE SYNTHESIS CAN ENHANCE CYCLOHEXIMIDE-INDUCEDPROTECTION OF DEVELOPING NEURONS AGAINST AXOTOMY, Developmental brain research, 102(2), 1997, pp. 285-290
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.