Abstract
BackgroundThe synthetic glucocorticoid dexamethasone (DEX) is commonly used to prevent chronic lung disease in prematurely born infants. Treatment regimens usually consist of high doses of DEX for several weeks, notably during a critical period of brain development. Therefore, there is some concern about adverse effects of this clinical practice on fetal brain development. In this study, using a clinically relevant rat model, we examined the impact of neonatal DEX treatment on subsequent brain injury due to an episode of cerebral hypoxia-ischemia (HI).ResultsWe found that a 3-day tapering course (0.5, 0.3 and 0.1 mg/kg) of DEX treatment in rat pups on postnatal days 1–3 (P1-3) exacerbated HI-induced brain injury on P7 by a glucocorticoid receptor-mediated mechanism. The aggravating effect of neonatal DEX treatment on HI-induced brain injury was correlated with decreased glutamate transporter-1 (GLT-1)-mediated glutamate reuptake. The expression levels of mRNA and protein of GLT-1 were significantly reduced by neonatal DEX treatment. We also found that the administration of β-lactam antibiotic ceftriaxone increased GLT-1 protein expression and significantly reduced HI-induced brain injury in neonatal DEX-treated rats.ConclusionsThese results suggest that early DEX exposure may lead the neonatal brain to be more vulnerable to subsequent HI injury, which can be ameliorated by administrating ceftriaxone.
Highlights
The synthetic glucocorticoid dexamethasone (DEX) is commonly used to prevent chronic lung disease in prematurely born infants
Neonatal DEX treatment enhances HI-induced brain injury To determine the influence of neonatal DEX treatment on HI-induced brain injury, we compared the infarction areas in coronal sections of SAL and DEX groups 24 hours after experimental HI (Figure 1A)
One-way ANOVA revealed a significant main effect of HI treatment on infarct volume (F3,25 = 15.3, P < 0.001), and post hoc analysis showed that infarct volume was significantly increased (P < 0.05) by neonatal DEX treatment compared with SAL-treated group (Figure 1C)
Summary
The synthetic glucocorticoid dexamethasone (DEX) is commonly used to prevent chronic lung disease in prematurely born infants. In this study, using a clinically relevant rat model, we examined the impact of neonatal DEX treatment on subsequent brain injury due to an episode of cerebral hypoxia-ischemia (HI). Chronic lung disease (CLD) is an important cause of mortality and morbidity in preterm infants and inflammation plays a major role in its pathogenesis [1,2] Due to their strong anti-inflammatory properties, synthetic glucocorticoids such as dexamethasone (DEX) or betamethasone are frequently used to prevent or lessen the morbidity of CLD in preterm infants. There is evidence that pretreatment of neonatal rats with DEX prevents brain injury associated with cerebral HI [14,15,16] These findings contrast with clinical observations that early DEX administration in preterm infants may increase the incidence of CP [4,5,6]. In this study, using a well established and clinically relevant 3-day tapering course of DEX treatment in neonatal rat pups on postnatal days 1–3 (P1-3) [9,14,17,18], we asked two main questions: (1) whether neonatal DEX treatment alters the vulnerability of the immature brain to HI-induced brain injury and (2) if so, what is the responsible molecular mechanism(s)
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