Increasing evidence indicates that
glucocorticoids (GCs), produced in response to physical/emotional stressors, can exacerbate brain damage resulting from
cerebral ischemia and severe seizure activity. However, much of the supporting evidence has come from studies employing nonphysiological paradigms in which adrenalectomized rats were compared with those exposed to constant GC concentrations in the upper physiological range.
Cerebral ischemia and
seizures can induce considerable GC secretion. We now present data from experiments using
metyrapone (an
11-beta-hydroxylase inhibitor of GC production), which demonstrate that the GC stress-response worsens subsequent brain damage induced by
ischemia and
seizures in rats. Three different paradigms of
brain injury were employed:
middle cerebral artery occlusion (MCAO) model of focal
cerebral ischemia; four-vessel occlusion (4VO) model of transient global forebrain
ischemia; and
kainic acid (KA)-induced (seizure-mediated) excitotoxic damage to hippocampal CA3 and CA1 neurons.
Metyrapone (200 mg/kg body wt) was administered systemically in a single i.p. bolus 30 min prior to each insult. In the MCAO model,
metyrapone treatment significantly reduced
infarct volume and also preserved cells within the
infarct. In the 4VO model, neuronal loss in region CA1 of the hippocampus was significantly reduced in rats administered
metyrapone. Seizure-induced damage to hippocampal pyramidal neurons (assessed by cell counts and immunochemical analyses of cytoskeletal alterations) was significantly reduced in rats administered
metyrapone. Measurement of plasma levels of
corticosterone (the species-typical GC of rats) after each insult showed that
metyrapone significantly suppressed the injury-induced rise in levels of circulating
corticosterone. These findings indicate that endogenous
corticosterone contributes to the basal level of
brain injury resulting from
cerebral ischemia and excitotoxic seizure activity and suggest that drugs that suppress
glucocorticoid production may be effective in reducing brain damage in
stroke and
epilepsy patients.