Hyperoxia induces the differentiated neuronal phenotype of PC12 cells by producing reactive oxygen species

Neurite extension of PC12 cells induced by nerve growth factor (NGF) is a well-known model of neuronal differentiation. In this study, the incubation of PC12 cells in a 50% O2 atmosphere (hyperoxia) caused neurite extension. In these cells, amounts of differentiation-marker proteins, tyrosine hydroxylase and neurofilament M increased. The effects of hyperoxia were inhibited by ascorbic acid or N-acetyl-cysteine, antioxidant reagents, suggesting the involvement of reactive oxygen species (ROS). In support of this, artificial generation of free radicals induced the same effects as hyperoxia. In these cells, total phosphorylation of cellular proteins was enhanced similar to NGF-treated cells. These results suggest that hyperoxia enhances the signal for neuronal differentiation by producing ROS, resulting in the induction of the differentiated neuronal phenotype of PC12 cells.