Dexamethasone aggravates ischemia-induced neuronal damage by facilitating the onset of anoxic depolarization and the increase in the intracellular Ca²⁺ concentration in gerbil hippocampus

The Ca²⁺ mobilization across the neuronal membrane is regarded as a crucial factor in the development of neuronal damage in ischemia. Because glucocorticoids have been reported to aggravate ischemic neuronal injury, the effects of dexamethasone on ischemia-induced membrane depolarization, histologic outcome, and changes in the intracellular Ca²⁺ concentration in the gerbil hippocampus were examined in vivo and in vitro. The effects of metyrapone, an inhibitor of glucocorticoid synthesis, were also evaluated. Changes in the direct current potential shift in the hippocampal CA1 area produced by transient forebrain ischemia for 2.5 minutes were compared among animals pretreated with dexamethasone (3 μg, intracerebroventricularly), metyrapone (100 mg/kg, intraperitoneally), and saline. The histologic outcome was evaluated 7 days after ischemia by assessing the delayed neuronal death in the hippocampal CA1 pyramidal cells of these animals. A hypoxia-induced intracellular Ca²⁺ increase was evaluated by in vitro microfluorometry in gerbil hippocampal slices, and the effect of dexamethasone (120 μg/L in the medium) on the cytosolic Ca²⁺ accumulation was examined. The effect in a Ca²⁺-free ischemialike condition was also investigated. Preischemic administration of dexamethasone reduced the onset latency of ischemia- induced membrane depolarization by 22%, and aggravated neuronal damage in vivo. In contrast, pretreatment with metyrapone improved the histologic outcome. The onset time of the increase in the intracellular concentration of Ca²⁺ provoked by in vitro hypoxia was advanced in dexamethasonetreated slices. The Ca²⁺-free in vitro hypoxia reduced the elevation compared with that in the Ca²⁺-containing condition. Treatment with dexamethasone facilitated the increase on both the initiation and the extent in the Ca²⁺- free condition. Aggravation of ischemic neuronal injury by endogenous or exogenous glucocorticoids is thus thought to be caused by the advanced onset times of both the ischemia-induced direct-current potential shift and the increase in the intracellular Ca²⁺ concentration.