Metyrapone, an Inhibitor of Glucocorticoid Production, Reduces Brain Injury Induced by Focal and Global Ischemia and Seizures

Abstract

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.

Social stress exacerbates stroke outcome by suppressing Bcl-2 expression

“…Our data corroborate clinical studies in which poststroke cortisol concentrations were predictive of stroke outcome (10)(11)(12). Furthermore, experimental manipulations that increase blood corticosterone concentrations during or after cerebral ischemia increase infarct volume in rats (13), whereas manipulations that decrease corticosterone concentrations are neuroprotective (14,15). Thus, in both humans and rodents, elevated Fig.…”

“…In humans, post-stroke cortisol concentrations are predictive of stroke outcome; high cortisol is associated with increased morbidity and mortality (10)(11)(12). Furthermore, experimental manipulations in rats that increase blood corticosterone concentrations during or after cerebral ischemia also increase infarct volume (13), whereas surgical or pharmacological suppression of corticosterone concentrations is neuroprotective (14,15). It has been proposed that rather than killing neurons directly, exposure to high concentrations of corticosteroids typically induces a physiological state that renders neurons more susceptible to subsequent neurologic insults (16).…”

Social Stress Exacerbates Focal Cerebral Ischemia in Mice

“…Intraischemic treatment of rats with metyrapone, a drug that attenuates stress-induced corticosterone production during MCAO, reduces infarction volume in the cortex and striatum by approximately 50%. 21 In contrast, treatment with exogenous corticosterone daily, beginning at reperfusion, results in increased infarction volume in hippocampus, neocortex, and striatum after global cerebral ischemia. 19,22 Taken together, these studies suggest that there is a potentially wide temporal window during which elevated serum glucocorticoid concentrations can affect ischemia-induced neuronal death.…”

Delayed recovery and exaggerated infarct size by post-lesion stress in a rat model of focal cerebral stroke

“…Manipulation of circulating stress hormone levels confirms the role of stress in recovery from stroke. Pre-treatment with the corticosteroid synthesis inhibitor metyrapone acts neuro-protectively when given after MCAO in rats (Smith-Swintosky et al, 1997;Krugers et al, 1998Krugers et al, , 2000. In contrast, Risedal et al (1999) found that pre-lesion treatment with metyrapone did not influence infarct size, while post-lesion administration exacerbated infarct volume and motor deficits in rats.…”