Dual role of the NF-kappaB transcription factor in the death of immature neurons.
We have previously shown that the extent of axotomy-induced death of retinal ganglion cells is reduced by cycloheximide, an inhibitor of protein synthesis, and that an earlier sublethal oxidative insult induced by buthionine sulfoximine, a glutathione synthesis inhibitor, enhances the protective effects of cycloheximide. Thus, axotomy-induced ganglion cell death seems to involve an interaction between the redox status and genetic expression. The redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB) is a logical candidate for providing this interaction. In the present study, we injected intraocularly selective inhibitors of NF-kappaB in chick embryos either unlesioned, or after a unilateral tectal lesion, which axotomizes ganglion cells. The number of dying cells in the retina contralateral to the lesion was reduced in embryos receiving NF-kappaB inhibitors as compared with vehicle-injected controls. In contrast, the same NF-kappaB inhibitors administered as pretreatment before intraocular injection of buthionine sulfoximine and cycloheximide drastically raised neuronal death and induced fulgurant degenerative changes in the retina. The most parsimonious interpretation of our results is that in axotomized retinal ganglion cells of chick embryos NF-kappaB may have either death-promoting or death-inhibiting effects. We propose a theoretical model to explain these dual effects assuming the existence of parallel death pathways differently affected by NF-kappaB. These results may have implications for future redox-based therapeutic strategies for neuroprotection.
Castagné
V
V
Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Rue du Bugnon 9, 1005, Lausanne, Switzerland. vincent.castagne@inst.hospvd.ch
Lefèvre
K
K
Clarke
P G
PG
D000818:Animals; D019771:Axotomy; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D002642:Chick Embryo; D003513:Cycloheximide / Q000494:pharmacology; D005123:Eye; D005978:Glutathione / Q000037:antagonists & inhibitors; D007267:Injections; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution
D016328:NF-kappa B; D018696:Neuroprotective Agents; D020569:Proto-Oncogene Proteins c-rel; D019328:Buthionine Sulfoximine; D003513:Cycloheximide; D005978:Glutathione