Dexamethasone potentiates NMDA receptor-mediated neuronal injury in the postnatal rat.
The present study investigated the effect of a synthetic glucocorticoid, dexamethasone, on excitatory amino acid receptor-mediated neurotoxicity in the 7-day-old rat. Pretreatment with dexamethasone (0.7 mg/kg i.p.) 1 h prior to unilateral intrastriatal injection of excitotoxin enhanced damage resulting from N-methyl-D-aspartate (NMDA), but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), or kainate receptor activation. The glucocorticoid-induced enhancement of NMDA toxicity was dose dependent. The time of dexamethasone administration appeared critical since only treatment 1 h prior to, but not 24 h prior to, simultaneously with, or 1 h after NMDA injection, affected toxicity. The administration of the adrenal mineralocorticoid aldosterone, or the phospholipase A2 inhibitor mepacrine, did not affect excitotoxicity. Quantitative receptor autoradiography was performed to assess the effect of dexamethasone on NMDA-sensitive [3H]glutamate receptor binding. Neither pretreatment in vivo nor the addition of dexamethasone in vitro affected NMDA-sensitive binding in the striatum. Possible explanations for these observations are discussed.
Supko
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DE
Johns Hopkins University School of Medicine, Baltimore, MD.
Johnston
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MV
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000032:analysis; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007608:Kainic Acid / Q000633:toxicity; D008797:Metyrapone / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity; D018377:Neurotransmitter Agents / Q000378:metabolism; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D001786:Blood Glucose; D005971:Glutamates; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000450:Aldosterone; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003907:Dexamethasone; D003576:Electron Transport Complex IV; D011796:Quinacrine; D007608:Kainic Acid; D008797:Metyrapone