Postnatal steroid treatment and brain development

Baud, Olivier

doi:10.1136/adc.2003.028696

Cited by 64 publications

(29 citation statements)

References 59 publications

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“…Even multiple courses of antenatal GC treatment do not appear to confer significant neurodevelopmental risk at 2-3 years of age (45,54), although school-age follow-up studies are required to fully assess this issue. In contrast, many studies show that use of neonatal (i.e., postnatal) treatment with Dex leads to motor and intellectual deficits (3,4,6,20).…”

Section: Clinical Implications the Synthetic Gcs Dex And β-Methasonementioning

confidence: 99%

“…GCs are also used postnatally in neonates with life-threatening airway and pulmonary conditions as well as in children that require cardiac bypass. However, there is ongoing concern about detrimental effects of GCs on the developing brain that lead to cognitive impairment and cerebral palsy (3)(4)(5), particularly in infants who receive Dex in the postnatal period (6).…”

Section: Introductionmentioning

confidence: 99%

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Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Heine¹,

Rowitch²

2009

J. Clin. Invest.

136

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Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GCinduced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from P0 through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Gli1, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Importantly, 11βHSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11βHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.

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Section: Clinical Implications the Synthetic Gcs Dex And β-Methasonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Heine¹,

Rowitch²

2009

J. Clin. Invest.

136

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“…A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

mentioning

confidence: 99%

“…Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2).…”

mentioning

confidence: 99%

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Bruder

Lee²,

Raff³

2005

Journal of Applied Physiology

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treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids. J Appl Physiol 98: [981][982][983][984][985][986][987][988][989][990] 2005. First published November 12, 2004; doi:10.1152/japplphysiol.01029.2004.-Dexamethasone is used as treatment for a variety of neonatal syndromes, including respiratory distress. The present study utilized the power of comprehensive lipid profiling to characterize changes in lipid metabolism in the neonatal lung and brain associated with dexamethasone treatment and also determined the interaction of dexamethasone with hypoxia. A 4-day tapering-dose regimen of dexamethasone was administered at 0800 on postnatal days 3 (0.5 mg/kg), 4 (0.25 mg/kg), 5 (0.125 mg/kg), and 6 (0.05 mg/kg). A subgroup of rats was exposed to hypoxia from birth to 7 days of age. Dexamethasone treatment elicited numerous specific changes in the lipid profile of the normoxic lung, such as increased concentrations of saturated fatty acids in the phosphatidylcholine and cholesterol ester classes. These increases were more profound in the lungs of hypoxic pups. Additional increases in cardiolipin concentrations were also measured in lungs of hypoxic pups treated with dexamethasone. We measured widespread increases in serum lipids after dexamethasone treatment, but the effects were not equivalent between normoxic and hypoxic pups. Dexamethasone treatment in hypoxic pups increased 20:4n6 and 22:6n3 concentrations in the free fatty acid class of the brain. Our results suggest that dexamethasone treatment in neonates elicits specific changes in lung lipid metabolism associated with surfactant production, independent of changes in serum lipids. These findings illustrate the benefits of dexamethasone on lung function but also raise the potential for negative effects due to hyperlipidemia and subtle changes in brain lipid metabolism. hypoxia; glucocorticoid therapy; neonate INHALED AND SYSTEMIC GLUCOCORTICOIDS have been widely used to treat syndromes of perinatal distress, many of which have an inflammatory component requiring pharmacological therapy (3,7,23,25,53). Dexamethasone, a highly potent glucocorticoid, has been the treatment of choice for neonates who are hypoxic due to cardiopulmonary conditions such as bronchopulmonary dysplasia (2,13,33,46,50). A major motivation for this therapy is the promotion of surfactant production and lung maturation and to induce closure of the ductus arteriosus (6,34,43,45,47). Dexamethasone decreases the duration of ventilatory support and lowers the incidence of chronic lung disease (13,23,33,50).Dexamethasone therapy, however, may lead to unfavorable long-term sequelae, including decreases in neuromotor and cognitive function (4,15,30,36,37,55), and may also lead to left ventricular abnormalities and metabolic dysfunction (5,14,17,24). A report of lipid intolerance in infants treated with dexamethasone highlights this potential for long-term metabolic dysfunction (2). It is for these reasons that the use of dexamethasone in neonates is decreasing (39) and...

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“…High-dose postnatal glucocorticoid treatment has substantial adverse effects (1)(2)(3)(4)(5). However, recent studies have identified high-risk subgroups in which the benefits of the treatment could potentially overshadow the side effects.…”

Section: Discussionmentioning

confidence: 99%

Placental 11β-HSD2 Activity, Early Postnatal Clinical Course, and Adrenal Function in Extremely Low Birth Weight Infants

et al. 2006

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ABSTRACT:The placental enzyme 11␤-hydroxysteroid dehydrogenase-2 (11␤-HSD2) transforms maternal cortisol to inactive cortisone. Fetal glucocorticoid excess due to reduced 11␤-HSD2 activity could make small preterm infants susceptible to early adrenal insufficiency when the maternal cortisol source is no longer sustained. We assessed whether placental 11␤-HSD2 activity is related to early adrenal insufficiency and postnatal clinical course in extremely low birth weight (Ͻ1000 g) infants. Mean gestational age of the 44 infants was 26.6 wk (range, 23.7-32.0), birth weight was 747 g (440 -981), and relative birth weight was Ϫ1.9 SD (Ϫ4.9 to 1.0). We determined placental 11␤-HSD2 activity, baseline, and ACTHstimulated cortisol and assessed illness severity by the Score of Neonatal Acute Physiology (SNAP). One standard deviation decrease in placental 11␤-HSD2 activity corresponded to a 1.85 (95% CI 0.55 to 3.14; p ϭ 0.006) unit increase in SNAP score and 2.9 mm Hg decrease in minimum mean arterial pressure (95% CI 0.3 to 5.6 mm Hg; p ϭ 0.03). Placental 11␤-HSD2 activity was not associated with cortisol concentrations, although the confidence interval of the ACTH-stimulated cortisol was close to zero: 1 SD increase corresponded to 17% (Ϫ18% to 49%) increase in ACTH-stimulated cortisol. Moreover, a 1 SD decrease in enzyme activity was associated with a hazard ratio for postnatal glucocorticoid treatment of 1.63 (95% CI 1.00 to 2.65); p ϭ 0.05. In ELBW infants, lower placental 11␤-HSD2 activity is associated with more severe early postnatal illness and hypotension. Although an association with baseline or ACTH-stimulated cortisol was not seen, possible relationships with other components of the hypothalamic-pituitary-adrenal axis remain to be determined. (Pediatr Res 59: 575-578, 2006)

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Postnatal steroid treatment and brain development

Cited by 64 publications

References 59 publications

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids

Placental 11β-HSD2 Activity, Early Postnatal Clinical Course, and Adrenal Function in Extremely Low Birth Weight Infants

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