Protection against hypoxic-ischemic damage with corticosterone and dexamethasone: inhibition of effect by a glucocorticoid antagonist RU38486.
We investigated whether the neuroprotection provided by dexamethasone against neonatal hypoxic-ischemic damage can be inhibited by a glucocorticoid antagonist and whether corticosterone, the endogenous glucocorticoid in the rat, also provides protection. Rats (6 days old) were treated with either vehicle (0.1 ml/10 g), corticosterone (3.5-80 mg/kg, s.c.) or dexamethasone alone or in combination with RU38486 (20-80 mg/kg, s.c.) 15 min prior to dexamethasone (0.1 mg/kg, i.p.). At 7 days of age, cerebral hypoxia-ischemia was produced by right carotid artery ligation under anesthesia and subsequent exposure to 2 h of hypoxia. Damage was quantified from brains perfusion-fixed and processed 2 days later. The reduction in somatic growth, thymus weight and the relatively elevated blood glucose levels at the end of hypoxia-ischemia were inhibited by RU38486. The protective effect of dexamethasone was also prevented by RU38486 (P < 0.001). Similar to pre-treatment with dexamethasone, administration of corticosterone (40-80 mg/kg) markedly reduced the extent of infarction compared to vehicle-treated controls (P < 0.0001). Thus, the endogenous glucocorticoid in the rat also provides protection against hypoxic-ischemic damage. RU38486 inhibits the beneficial effects of dexamethasone demonstrating that the neuroprotection observed with dexamethasone is a glucocorticoid receptor-mediated effect.
Tuor
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Biosystems, Institute for Biodiagnostics, NRCC, Winnipeg, Man, Canada. tuor@ibd.nrc.ca
Del Bigio
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D000818:Animals; D003345:Corticosterone / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D005938:Glucocorticoids / Q000037:antagonists & inhibitors; D006727:Hormone Antagonists / Q000494:pharmacology*; D002534:Hypoxia, Brain / Q000188:drug therapy*; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D015735:Mifepristone / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*
D005938:Glucocorticoids; D006727:Hormone Antagonists; D018696:Neuroprotective Agents; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; D003345:Corticosterone