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Effect of dexamethasone treatment on maturational changes in the NMDA receptor in sheep brain
J E McGowan1, G Sysyn, K H Petersson
1Department of Pediatrics, MCP Hahnemann University and St. Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134, USA.jmcgowan@jhmi.edu.
Abstract:
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.
Insights
Corticosteroid treatment affects the N-methyl-D-aspartate (NMDA) receptor in developing lambs, reducing receptor number and affinity. This indicates a critical window for corticosteroid impact on brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The N-methyl-D-aspartate (NMDA) receptor is crucial for normal brain development and hypoxic-ischemic injury.
- Corticosteroids are frequently administered during pregnancy and to newborns.
Purpose of the Study:
- To investigate the impact of antenatal and postnatal corticosteroid exposure on the NMDA receptor in developing lambs.
- To determine how dexamethasone treatment affects NMDA receptor binding characteristics (MK-801 binding site) during different developmental stages.
Main Methods:
- Utilized (3)H-MK-801 binding assays on cerebral cortical cell membranes from fetal, newborn (5-day-old), and adult sheep.
- Administered dexamethasone or placebo to pregnant ewes and newborn lambs at varying doses.
- Analyzed changes in B(max) (receptor number) and K(d) (receptor affinity).
Main Results:
- NMDA receptor number (B(max)) increased during development, peaking in 5-day-old lambs, while affinity (K(d)) remained constant.
- Dexamethasone treatment did not affect NMDA receptor binding in fetuses or adults.
- In lambs, dexamethasone significantly decreased B(max) and receptor affinity for MK-801.
Conclusions:
- Dexamethasone exposure modifies NMDA receptor characteristics specifically during a sensitive postnatal developmental period in lambs.
- These findings suggest a potential vulnerability of the developing brain to corticosteroid-induced alterations in NMDA receptor function.