The Corticosterone Synthesis Inhibitor Metyrapone Prevents Hypoxia/Ischemia-Induced Loss of Synaptic Function in the Rat Hippocampus

Abstract

Background and Purpose-Ischemia is accompanied by abundant corticosterone secretion, 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 glucocorticoid 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). Convulsions were monitored after HI, and 24 hours later, field potentials were recorded in vitro in the hippocampal CA1 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 with steroid treatment before HI. Results-Metyrapone suppressed plasma corticosteroid levels during HI, whereas corticosterone treatment significantly elevated plasma steroid levels. These treatments affected the incidence of visible seizures after HI: corticosterone treatment resulted in the highest incidence, whereas metyrapone attenuated the occurrence of seizures. Moreover, the HI-induced impairment in synaptic transmission in the CA1 area in vitro was exacerbated by concomitant corticosteroid treatment and alleviated by pretreatment with metyrapone. 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 seizures shortly after ischemia. Conclusions-We tentatively conclude that synaptic function along with cellular integrity is preserved after HI by preventing the ischemia-evoked rise in corticosteroid levels rather than blocking the glucocorticoid receptor.

Chronic Unpredictable Stress Exacerbates Lipopolysaccharide-Induced Activation of Nuclear Factor-κB in the Frontal Cortex and Hippocampus via Glucocorticoid Secretion

“…Prolonged stress or exposure to stress levels of GCs can impair the ability of hippocampal and cortical neurons to survive various insults (Stein-Behrens et al, 1992;Krugers et al, 2000;Madrigal et al, 2003) and can augment insult-induced glutamate release and NMDA receptor activation (Armanini et al, 1990;Moghaddam et al, 1994;Madrigal et al, 2001b). Stress itself can increase glutamate release in both regions and inhibit its uptake by glial transporters (Chou et al, 1994).…”

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

“…Direct effects of glucocorticoids on the motor system might represent one of the pathways mediating the effects of stress on motor recovery after stroke. Earlier studies provide support for this notion by showing that administration of exogenous glucocorticoids (Sapolsky and Pulsinelli, 1985;Sugo et al, 2002), the glucocorticoid receptor antagonist mifepristone (Risedal et al, 1999;Sugo et al, 2002), or the steroid synthesis inhibitor metyrapone (Smith-Swintosky et al, 1997; Krugers et al, 2000) affects the outcome of ischemic lesions in rodents. The relationship between reaching success, recovery and corticosterone levels in the present study was weak, particularly with regard to group differences found in baseline blood samples.…”

“…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.…”

Malocclusion induces chronic stress

“…To confirm that GCs (specifically CO) induce functional and morphologic changes in the hippocampus, a GCs synthesis inhibitor, metyrapone 22,23) , was administered to mice, and the effects of the bite-raised condition on Morris water maze training and the number of hippocampal neurons were examined 9) . Metyrapone administered to 9-month-old bite-raised mice attenuated the increase in the blood CO concentration, as well as the impaired performance in the Morris water maze, and hippocampal cell death 9) .…”