METYRAPONE, AN INHIBITOR OF GLUCOCORTICOID PRODUCTION, REDUCES BRAIN INJURY-INDUCED BY FOCAL AND GLOBAL-ISCHEMIA AND SEIZURES

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 nonph ysiological paradigms in which adrenalectomized rats were compared wit h those exposed to constant GC concentrations in the upper physiologic al range, Cerebral ischemia and seizures can induce considerable GC se cretion, We now present data from experiments using metyrapone (an 11- beta-hydroxylase inhibitor of GC production), which demonstrate that t he GC stress-response worsens subsequent brain damage induced by ische mia and seizures in rats. Three different paradigms of brain injury we re employed: middle cerebral artery occlusion (MCAO) model of focal ce rebral ischemia; four-vessel occlusion (4VO) model of transient global forebrain ischemia; and kainic acid (KA)-induced (seizure-mediated) e xcitotoxic 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 sig nificantly reduced infarct volume and also preserved cells within the infarct. In the 4VO model, neuronal loss in region CA1 of the hippocam pus was significantly reduced in rats administered metyrapone, Seizure -induced damage to hippocampal pyramidal neurons (assessed by cell cou nts and immunochemical analyses of cytoskeletal alterations) was signi ficantly reduced in rats administered metyrapone. Measurement of plasm a levels of corticosterone (the species-typical GC of rats) after each insult showed that metyrapone significantly suppressed the injury-ind uced rise in levels of circulating corticosterone. These findings indi cate 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 productio n may be effective in reducing brain damage in stroke and epilepsy pat ients.