An optimal redox status for the survival of axotomized ganglion cells in the developing retina.
The neuronal redox status influences the expression of genes involved in neuronal survival. We previously showed that antioxidants may reduce the number of dying ganglion cells following axotomy in chick embryos. In the present study, we show that various antioxidants, including the new spin trap azulenyl nitrone and 1,3-dimethyl-2-thiourea, protect axotomized ganglion cells, confirming that neuronal death involves an imbalance of the cellular redox status towards oxidation. However, high concentrations of antioxidants did not protect ganglion cells, suggesting that excessive reduction is detrimental for neurons. Simultaneous injections of two different antioxidants gave results only partly supporting this view. Combinations of azulenyl nitrone and N-acetyl cysteine in fact gave greater protection than either antioxidant alone, whereas N-acetyl cysteine lost its neuroprotective effects and diminished those of alpha-phenyl-N-tert-butyl nitrone when the two compounds were injected simultaneously. The results of the combined treatments suggest that azulenyl nitrone and alpha-phenyl-N-tert-butyl nitrone do not have the same chemical effects within the ganglion cells. Moreover, N-acetyl cysteine's own antioxidant properties enhance the spin trapping effects of azulenyl nitrone but potentiate the toxicity of alpha-phenyl-N-tert-butyl nitrone. Our main conclusion is that neuronal survival requires the maintenance of the redox status near an optimal set-point. "Reductive stress" may be as dangerous as oxidative stress.
Castagné
V
V
Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Switzerland.
Lefèvre
K
K
Natero
R
R
Clarke
P G
PG
Bedker
D A
DA
D000111:Acetylcysteine / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019771:Axotomy; D052176:Azulenes; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D003497:Cyclic N-Oxides; D005123:Eye / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000493:pharmacokinetics / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D012160:Retina / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D012162:Retinal Degeneration / Q000503:physiopathology / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
D000975:Antioxidants; D052176:Azulenes; D003497:Cyclic N-Oxides; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D012717:Sesquiterpenes; C113630:azulenyl nitrone; C029217:phenyl-N-tert-butylnitrone; C038983:1,3-dimethylthiourea; D013890:Thiourea; D000111:Acetylcysteine