The corticosterone synthesis inhibitor metyrapone prevents hypoxia/ischemia-induced loss of synaptic function in the rat hippocampus

Background and Purpose-Ischemia is accompanied by abundant corticosterone s ecretion, which could potentially exacerbate brain damage via activation of glucocorticoid receptors. We addressed whether manipulating steroid levels during ischemia affects hippocampal synaptic function along with neuronal structure. Moreover, we established whether pretreatment with the glucocort icoid receptor antagonist RU38486 is as effective in preventing deleterious effects after ischemia as is the steroid synthesis inhibitor metyrapone. Methods-Rats underwent 20 minutes of unilateral hypoxia/ischemia (HI). Conv ulsions were monitored after HI, and 24 hours later, field potentials were recorded in vitro in the hippocampal CAI area in response to stimulation of the Schaffer collateral/commissural fibers. Morphological alterations were determined in brain slices from the same animals. Data were correlated wit h steroid treatment before HI. Results-Metyrapone suppressed plasma corticosteroid levels during HI, where as corticosterone treatment significantly elevated plasma steroid levels. T hese treatments affected the incidence of visible seizures after PII: corti costerone treatment resulted in the highest incidence, whereas metyrapone a ttenuated the occurrence of seizures. Moreover, the HI-induced impairment i n synaptic transmission in the CA1 area in vitro was exacerbated by concomi tant corticosteroid treatment and alleviated by pretreatment with metyrapon e. In parallel, degenerative changes in the hippocampus after HI were most pronounced after corticosterone treatment, whereas metyrapone reduced these alterations. RU38486 was effective only in reducing the incidence of seizu res shortly after ischemia. Conclusions-We tentatively conclude that synaptic function along with cellu lar integrity is preserved after HI by preventing the ischemia-evoked rise in corticosteroid levels rather than blocking the glucocorticoid receptor.