ObjectiveTo investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn.Patients and MethodsIncluded were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids.The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage.ResultsThe hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage.ConclusionWe found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.
Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.
In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1 mg.kg−1.day−1), with or without antioxidant vitamins C and E (DEXCE; 200 mg.kg−1.day−1 and 100 mg.kg−1.day−1, respectively), on postnatal days 1–6 (P1–6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm3 vs. 564.0±20.0 mm3), the soma volume of neurons in the CA1 (1172.6±30.4 µm3 vs. 1002.4±11.8 µm3) and in the dentate gyrus (525.9±27.2 µm3 vs. 421.5±24.6 µm3) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm3), and soma volume of neurons in the CA1 (1157.5±42.4 µm3) and the dentate gyrus (536.1±27.2 µm3). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.
ObjectiveAlthough postnatal corticosteroid (CS) therapy has well established beneficial effects on pulmonary function, it may also result in growth restriction during treatment. The course of early childhood growth is believed to predict cardiovascular and metabolic diseases in adulthood. Therefore, we determined the effects of postnatal dexamethasone (DEX) or hydrocortisone (HC) treatment on patterns of postnatal growth until approximately four years of age.Study designIn an observational cohort study of children born prematurely (<32 weeks of gestation), we compared growth patterns for body weight, height, and head circumference from birth to age four years, of children who received DEX (boys: N = 30, girls: N = 14), HC (boys: N = 33, girls: N = 28) to a reference group that had not received postnatal CSs (boys: N = 52, girls: N = 53) using linear mixed-effects modeling.ResultsGrowth velocity curves of CS-treated neonates showed a shift to the right, representing a delay in time. They had decreased absolute growth velocities during and shortly after treatment, followed by an increase in growth velocity thereafter. A shift to the right was also seen for the age at which maximal growth velocity of weight/height was reached in boys and girls. Fractional growth rates of weight, height, and head circumference were generally reduced in the CS-treated groups during the first two months of age, with catch-up growth in the following months. In DEX-treated infants these changes were more pronounced than in HC-treated infants.ConclusionThese data suggest that postnatal growth patterns of preterm born infants are affected by CS-treatment, more by DEX than by HC. Effects were observed mainly on growth velocities. This observation may have impact on health in later life for those individuals treated with CSs in the neonatal period. A definitive conclusion would require a randomized trial of these therapies.
Background: Postnatal glucocorticoid therapy in the treatment of chronic lung disease benefits lung function, however it adversely affects brain development. We hypothesized that combined postnatal glucocorticoid and statin therapy diminishes adverse effects of glucocorticoids on the developing brain. Methods: On postnatal days (P) 1-3, one male pup per litter received i.p. injections of saline (control (C), n = 13) or dexamethasone (0.5, 0.3, 0.1 µg/g; D, n = 13), ± pravastatin (10 mg/ kg i.p.; CP, n = 12; DP, n = 15). Statins or saline continued from P4-6. At P21, brains were perfusion fixed for histological and stereological analyses. results: Relative to controls, dexamethasone reduced total (837 ± 23 vs. 723 ± 37), cortical (378 ± 12 vs. 329 ± 15), and deep gray matter (329 ± 12 vs. 284 ± 15) volume (mm 3 ), cortical neuronal number (23 ± 1 vs. 19 ± 1 × 10 6 ), and hippocampal neuronal soma volume (CA1: 1,206 ± 32 vs. 999 ± 32; dentate gyrus: 679 ± 28 vs. 542 ± 24 µm 3 ; all P < 0.05). Dexamethasone increased the glial fibrillary acidic protein-positive astrocyte density in the white matter (96 ± 2 vs. 110 ± 4/0.1 mm 2 ); P < 0.05. These effects no longer occurred in brains from pups treated with combined dexamethasone and pravastatin. Pravastatin alone had no effect on these variables. conclusion: Concomitant dexamethasone with statins in premature infants may be safer for the developing brain than dexamethasone alone in the treatment of chronic lung disease. c hronic lung disease is a common outcome in extremely preterm neonates with severe respiratory distress syndrome and carries a high incidence of morbidity and mortality (1). Glucocorticoids, predominantly dexamethasone, are used to decrease inflammatory responses, accelerate surfactant production, and lung maturation, thereby improving respiratory function (2).Despite the well-established beneficial effects of postnatal glucocorticoid therapy, there has been serious growing concern regarding their clinical use because of unwanted side effects on somatic growth and weight gain in premature babies (3,4). Accumulating evidence from clinical trials has also demonstrated an association between postnatal steroid therapy and adverse neuromotor and cognitive outcomes (4,5). Furthermore, experimental studies in neonatal animals have demonstrated adverse effects of potent glucocorticoids, such as dexamethasone, on brain growth, cell division, differentiation, myelination, apoptosis, and neurogenesis (6-8).To date, the mechanism underlying the unwanted side effects of glucocorticoid therapy on the developing brain remains unknown, preventing the identification of plausible modified therapies to maintain the beneficial, but prevent the adverse, effects of steroid treatment. Glucocorticoids are known to decrease nitric oxide (NO) bioavailability and increases in NO via antioxidant treatment have been shown to prevent or partially restore glucocorticoid-induced cardiovascular dysfunction and hypertension (9,10), implying impaired NO physiology as the culprit mecha...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.