Effect of dexamethasone treatment on maturational changes in the NMDA receptor in sheep brain.
The objective of the present study was to examine the effect of antenatal or postnatal treatment with corticosteroids on the NMDA receptor, one of the mediators of both normal brain development and hypoxic-ischemic injury, by determining the characteristics of the receptor MK-801 binding site in untreated and corticosteroid-treated fetal and newborn lambs. (3)H-MK-801 binding was performed in cerebral cortical cell membranes from fetal sheep at 88, 120, and 136 d gestation (term = 150 d), and from 5-d-old lambs and adult ewes. Animals were randomized to receive dexamethasone [fetuses: 6 mg, i.m. every 12 hr for four doses to mother; lambs: 0.01 mg/kg (low dose) or 0.25 mg/kg (high dose) every 12 hr for four doses] or placebo. During development, B(max) (apparent number of receptors) increased, reaching a maximum in 5-d-old lambs (p < 0.05) and decreasing in the adult brain. K(d) (dissociation constant) did not change, suggesting that receptor affinity was not altered during maturation. Dexamethasone treatment had no effect on MK-801 binding in the fetus or adult, but in lambs was associated with a significant decrease in B(max) from 2.17 +/- 0.18 pmol/mg protein in placebo-treated animals to 1.65 +/- 0.8 and 1.62 +/- 0.07 pmol/mg protein in low-dose and high-dose animals, respectively. Affinity for (3)H-MK-801 decreased 20% after dexamethasone treatment in lambs only (p < 0.05). Thus, dexamethasone treatment appears to modify the NMDA receptor only during a specific period of brain development.
McGowan
J E
JE
Department of Pediatrics, MCP Hahnemann University and St. Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, USA.jmcgowan@jhmi.edu.
Sysyn
G
G
Petersson
K H
KH
Sadowska
G B
GB
Mishra
O P
OP
Delivoria-Papadopoulos
M
M
Stonestreet
B S
BS
D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D001784:Blood Gas Analysis; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005865:Gestational Age; D006339:Heart Rate / Q000187:drug effects; D006854:Hydrocortisone / Q000097:blood; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012756:Sheep
D001786:Blood Glucose; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003907:Dexamethasone; D006854:Hydrocortisone