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Published on: November 20, 2015
Context modulates outcome of perinatal glucocorticoid action in the brain
E Ronald de Kloet1, Sanne E F Claessens2, Jiska Kentrop2
1Department of Medical Pharmacology, Leiden University Medical Center, Leiden University , Leiden , Netherlands ; Department of Endocrinology and Metabolism, Leiden University Medical Center , Leiden , Netherlands.
Insights
Glucocorticoid treatment for premature infants can accelerate tissue development but may increase later-life risks. Factors like steroid type, timing, and environmental context influence these outcomes in the developing brain.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Premature infants often require glucocorticoids to aid tissue maturation, especially lung development.
- While life-saving, early glucocorticoid exposure is linked to adverse long-term outcomes.
- Previous studies suggest reduced lifespan in rodents treated with dexamethasone, though findings vary.
Purpose of the Study:
- To investigate how perinatal glucocorticoid exposure impacts the developing brain in rodent models.
- To explore the influence of steroid type, timing, and environmental context on these effects.
- To identify potential clinical implications for treating premature infants.
Main Methods:
- Review of rodent studies examining perinatal glucocorticoid administration.
- Analysis of factors influencing glucocorticoid effects: steroid type, timing of exposure, and environmental context.
- Consideration of receptor binding (mineralocorticoid and glucocorticoid receptors) and placental inactivation (11β-HSD type 2).
Main Results:
- Glucocorticoid effects on the brain are context- and timing-dependent.
- Synthetic glucocorticoids like dexamethasone primarily bind to glucocorticoid receptors (GR).
- Environmental factors (e.g., early handling, maternal care) can mitigate adverse effects of postnatal dexamethasone.
- Early-life exposure may epigenetically program later-life coping mechanisms.
Conclusions:
- Perinatal glucocorticoid administration requires careful consideration of steroid type, timing, and environmental context.
- Understanding these determinants is crucial for optimizing treatment strategies for premature infants.
- Further research may refine clinical practices to minimize long-term risks associated with neonatal glucocorticoid therapy.
Abstract:
Prematurely born infants may be at risk, because of inadequate maturation of tissues. If there are signs of preterm birth, it has become common practice therefore to treat either antenatally the mother or postnatally the infant with glucocorticoids to accelerate tissue development, particularly of the lung. However, this life-saving early glucocorticoid treatment was found to increase the risk of adverse outcome in later life. In one animal study, the authors reported a 25% shorter lifespan of rats treated as newborns with the synthetic glucocorticoid dexamethasone, but so far this finding has not been replicated. After a brief clinical introduction, we discuss studies in rodents designed to examine how perinatal glucocorticoid action affects the developing brain. It appears that the perinatal action of the glucocorticoid depends on the context and the timing as well as the type of administered steroid. The type of steroid is important because the endogenous glucocorticoids cortisol and corticosterone bind to two distinct receptor populations, i.e., mineralocorticoid and glucocorticoid receptors (GR), while synthetic glucocorticoids predominantly bind to the GR. In addition, if given antenatally hydrocortisone is inactivated in the placenta by 11β-HSD type 2, and dexamethasone is not. With respect to timing, the outcome of glucocorticoid effects is different in early vs. late phases of brain development. The context refers to the environmental input that can affect the susceptibility to glucocorticoid action in the newborn rodent brain; early handling of pups and maternal care obliterate effects of post-natal dexamethasone treatment. Context also refers to coping with environmental conditions in later life, for which the individual may have been programed epigenetically by early-life experience. This knowledge of determinants affecting the outcome of perinatal glucocorticoid exposure may have clinical implications for the treatment of prematurely born infants.
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