Inhibition of glutathione depletion by retinoic acid and tocopherol protects cultured neurons from staurosporine-induced oxidative stress and apoptosis.
Cellular redox status is an important factor during neuronal apoptosis. In primary cultures of chick embryonic neurons, serum deprivation and treatment with staurosporine (200 nM) for 24 h increased the percentage of apoptotic neurons from 13% in controls to 28%, and 68%, respectively. Both exposure to staurosporine and serum deprivation resulted in a four-fold increase in the mitochondrial reactive oxygen species production 4 h after the onset of the injury. Whereas the intracellular glutathione content remained unchanged by serum deprivation, it was markedly reduced by staurosporine suggesting that an increased reactive oxygen species production was more deleterious at a low intracellular glutathione content. Treatment with L-buthionine-(S,R)-sulfoximine, an inhibitor of the glutathione synthesis, decreased the intracellular glutathione content, but did not significantly alter the percentage of apoptotic neurons. Tocopherol (10 microM) and retinoic acid (0.1 microM) inhibited staurosporine-induced glutathione depletion as well as the increase in the percentage of apoptotic neurons. We conclude that under conditions of an increased reactive oxygen species production a high intracellular glutathione content could protect neurons from apoptotic injury and that drugs inhibiting the glutathione depletion could prevent neurons from oxidative damage.
Ahlemeyer
B
B
Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der Philipps-Universität Marburg, Germany. ahlemeye@mailer.uni-marburg.de
Krieglstein
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D016895:Culture Media, Serum-Free; D005978:Glutathione / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013687:Telencephalon / Q000166:cytology / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D014810:Vitamin E; D014212:Tretinoin; D005978:Glutathione; D019311:Staurosporine