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Development of glucocorticoid receptor regulation in the rat forebrain: implications for adverse effects of glucocorticoids in preterm infants.

Publication ,  Journal Article
Slotkin, TA; Seidler, FJ; Wood, CR; Lau, C
Published in: Brain Res Bull
July 30, 2008

Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoid-induced disruption in the fetus than in the neonate. Feedback regulation of glucocorticoid receptors (GRs) is an essential homeostatic mechanism and we therefore examined the development of GR downregulation in the perinatal period. Pregnant rats or newborn pups were given dexamethasone daily (gestational days 17-19, postnatal days 1-3, or postnatal days 7-9), ranging from doses below that recommended for use in preterm infants (0.05 mg/kg) to therapeutic doses (0.2 or 0.8 mg/kg). Twenty-four hours after the last injection, we determined forebrain GR protein by Western blotting. Although postnatal dexamethasone treatment downregulated GRs at all doses, the fetal forebrain failed to show any decrement and instead exhibited slight GR upregulation. In controls, forebrain GR levels also showed a large increment over the course from late gestation through the second postnatal week, despite the fact that circulating glucocorticoid levels increase substantially during this period. Our results suggest that GR homeostasis develops primarily postnatally and that fetal inability to downregulate GRs in the face of exogenous glucocorticoid administration plays a role in the vulnerability of key neural circuits to developmental disruption. Since this developmental phase in the rat corresponds to the critical period in which glucocorticoids are used in preterm infants, adverse effects on brain development may be inescapable.

Duke Scholars

Published In

Brain Res Bull

DOI

EISSN

1873-2747

Publication Date

July 30, 2008

Volume

76

Issue

5

Start / End Page

531 / 535

Location

United States

Related Subject Headings

  • Receptors, Glucocorticoid
  • Rats, Sprague-Dawley
  • Rats
  • Prosencephalon
  • Pregnancy
  • Neurology & Neurosurgery
  • Male
  • Infant, Premature
  • Infant, Newborn
  • Humans
 

Citation

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Slotkin, T. A., Seidler, F. J., Wood, C. R., & Lau, C. (2008). Development of glucocorticoid receptor regulation in the rat forebrain: implications for adverse effects of glucocorticoids in preterm infants. Brain Res Bull, 76(5), 531–535. https://doi.org/10.1016/j.brainresbull.2008.03.002
Slotkin, Theodore A., Frederic J. Seidler, Carmen R. Wood, and Christopher Lau. “Development of glucocorticoid receptor regulation in the rat forebrain: implications for adverse effects of glucocorticoids in preterm infants.Brain Res Bull 76, no. 5 (July 30, 2008): 531–35. https://doi.org/10.1016/j.brainresbull.2008.03.002.
Slotkin, Theodore A., et al. “Development of glucocorticoid receptor regulation in the rat forebrain: implications for adverse effects of glucocorticoids in preterm infants.Brain Res Bull, vol. 76, no. 5, July 2008, pp. 531–35. Pubmed, doi:10.1016/j.brainresbull.2008.03.002.
Journal cover image

Published In

Brain Res Bull

DOI

EISSN

1873-2747

Publication Date

July 30, 2008

Volume

76

Issue

5

Start / End Page

531 / 535

Location

United States

Related Subject Headings

  • Receptors, Glucocorticoid
  • Rats, Sprague-Dawley
  • Rats
  • Prosencephalon
  • Pregnancy
  • Neurology & Neurosurgery
  • Male
  • Infant, Premature
  • Infant, Newborn
  • Humans