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 microg, 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 microg/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 dexamethasone-treated 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.
Adachi
N
N
Department of Anesthesiology and Resuscitology, Ehime University School of Medicine, Shigenobu, Japan.
Chen
J
J
Liu
K
K
Tsubota
S
S
Arai
T
T
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D005849:Gerbillinae; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D009474:Neurons / Q000473:pathology*
D005938:Glucocorticoids; D003907:Dexamethasone; D002118:Calcium