Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture

Abstract

Glucocorticoids (GCs), the adrenal steroids secreted during stress, are known to affect diverse processes involving reactive oxygen species, from exacerbation of ischemic damage to alteration of antioxidant enzyme activities. To determine whether GCs have a direct effect on oxidative processes, we constructed a dose-response curve using adriamycin, an oxygen radical generator, in primary neuronal cultures. In cultures derived from the hippocampus, which has the greatest concentration of corticosteroid receptors in the brain, higher levels of GCs significantly increased adriamycin toxicity, while not being toxic themselves. In cortical cultures, which contain lesser amounts of corticosteroid receptors, GCs had no effect on the adriamycin dose-response. Surprisingly, when tested with dichlorofluorescein for levels of reactive oxygen species (ROS), GCs increased ROS by approximately 10% basally and at all adriamycin doses in both hippocampal and cortical cultures. Thus, greater generation of ROS does not account for the increased susceptibility of the hippocampus to oxidative damage.