Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

Bennet, Laura; Davidson, Joanne O.; Koome, Miriam; Gunn, Alistair Jan

doi:https://doi.org/10.1155/2012/751694

Journal of Pregnancy

On this page

Abstract Introduction Conclusions Acknowledgments References Copyright Related Articles

Special Issue

Basic Experimental and Clinical Advances in the Mechanisms Underlying Abnormal Pregnancy Outcomes

View this Special Issue

Review Article | Open Access

Volume 2012 | Article ID 751694 | https://doi.org/10.1155/2012/751694

Glucocorticoids and Preterm Hypoxic-Ischemic Brain Injury: The Good and the Bad

Laura Bennet,¹Joanne O. Davidson,¹Miriam Koome,¹and Alistair Jan Gunn¹

Academic Editor: Janna Morrison

Received27 Mar 2012

Accepted13 Jul 2012

Published16 Aug 2012

Abstract

Fetuses at risk of premature delivery are now routinely exposed to maternal treatment with synthetic glucocorticoids. In randomized clinical trials, these substantially reduce acute neonatal systemic morbidity, and mortality, after premature birth and reduce intraventricular hemorrhage. However, the overall neurodevelopmental impact is surprisingly unclear; worryingly, postnatal glucocorticoids are consistently associated with impaired brain development. We review the clinical and experimental evidence on how glucocorticoids may affect the developing brain and highlight the need for systematic research.

1. Introduction

Since Liggins and Howie [1] showed that antenatal glucocorticoids play an important role in the prevention of respiratory distress syndrome in premature infants, antenatal glucocorticoids have been increasingly given to women at risk of premature delivery. In 1994, the National Institutes of Health Consensus Conference stated that all fetuses between 24 and 34 weeks of gestation at risk of premature delivery should be considered candidates for treatment with antenatal glucocorticoids [2]. Meta-analysis of randomized clinical trials suggests that maternal treatment with antenatal glucocorticoids substantially reduces acute neonatal systemic morbidity, and mortality, after premature birth and reduces intraventricular hemorrhage [3]. There is some evidence from individual studies that treatment may also reduce the risk of white matter injury [4, 5].

2. Cause for Concern?

There is limited information on the short-term and long-term effects of antenatal glucocorticoids on the brain. From animal studies there is some evidence that antenatal glucocorticoids may cause impairment of neural development [6]. These side effects include alterations of neuronal cytoskeleton and presynaptic terminals [7–9], delay in myelination [10, 11], alterations in proliferation [12], decrease in cerebral blood flow [13], alterations in neuronal activity [14], and brain growth retardation [15].

In humans, antenatal glucocorticoids were associated with an increased risk of disorders in aggressive destructive behaviour, hyperactivity, and distractibility [16]. However, results are not consistent in different studies. MacArthur and colleagues [17, 18] found no effect of betamethasone treatment on cognitive development of 4-year-old children and cognitive development and school progress of 6-year-old children. After a 10- to 12-year followup, children who were treated with antenatal glucocorticoids did not differ from controls in growth, lung function, development of sexual characteristics, sleep quality, incidence of physical anomalies, and neurological status [19]. Murphy found no brain growth retardation in babies delivered preterm who died [20].

In contrast, there is now considerable experimental and clinical evidence that postnatal administration to preterm infants is consistently associated with impaired brain development [21]. In rodents glucocorticoids are associated with reduced proliferation and a decrease in total cell numbers, leading to impaired brain growth and development [5, 7–9, 12, 15, 22–28]. Indeed, in rodents exposure to glucocorticoids before or immediately after birth may be associated with marked upregulation of neuronal and progenitor cell apoptosis, particularly in the hippocampus where they deplete the pool of neural progenitor cells and reduce hippocampal growth [29–31]. In turn, there is increasing evidence that exposure of neonates to exogenous glucocorticoids impairs memory and increases the risk of CP [32].

Pragmatically, the effects of prenatal and postnatal exposure are of course unlikely to be identical. The duration of maternal treatment is much shorter (typically 2 to 4 doses over 24 h versus 3 to 42 days of daily treatment [33]) and given the role of the placenta, it is likely that the profile of fetal plasma concentrations would be lower than after maternal administration compared with postnatal treatment. Nevertheless, these data strongly suggest that it is vital to understand how glucocorticoids affect the developing brain [22].

3. Cerebral Palsy after Preterm Birth

Cerebral palsy (CP) associated with premature birth now accounts for over a third of total cases [34]. The costs to society are huge. CP has one of the very highest indices of burden of disease from loss of potential productive members of society and direct burdens on the individual, family, and social institutions that last the entire life [35]. In the USA, 13% of all births are preterm, costing over $26.2 billion in 2005 alone [36]. There has been little or no reduction in the incidence of CP of perinatal origin, and the risk may even have increased in some Western countries [36], despite 35 years of advances in perinatal care. Most of these costs are related to long-term neurodevelopmental disability in surviving infants, rather than acute care after birth [37–39]. Although there has been a reduction in the most severe form of cystic white matter injury over time [40], even subtle injury is associated with impaired brain development and disability [38, 41]. It is striking that risk of injury and disability are increased sevenfold even in “late preterm” infants of 34 to 36 weeks gestation [42–45]. Thus, even small changes in the risk of disability would have substantial real-world impact.

4. What Causes Injury after Preterm Birth?

Although the etiology of neurodevelopmental disability after preterm birth is undoubtedly multifactorial, there is considerable evidence that exposure to perinatal hypoxia-ischemia (HI) is a major trigger [46]. In turn, this may be augmented or modulated by prior exposure to hypoxia, infection/inflammation, seizures, and placental damage [47–52]. In addition, babies are exposed to many clinical interventions. Notably, unborn children are now routinely exposed to maternal treatment with potent synthetic glucocorticoids. Although steroid treatment is one of the most cost effective, live-saving treatments in fetal medicine, it is not without potential risks for some fetuses.

5. Betamethasone versus Dexamethasone

It has been much debated whether there is any material difference in neonatal outcomes between two major synthetic glucocorticoids used for antenatal treatment, despite these compounds differing only in the orientation of one methyl group. For example, it has been suggested that betamethasone, but not dexamethasone can reduce the risk of periventricular leukomalacia in very premature infants [4]. Further, betamethasone has been associated with better survival and reduced risk of adverse outcomes [53], and with better neurodevelopment and fewer hearing problems [54]. In contrast, others found no differences [55, 56], and one study suggested that dexamethasone reduced the risk for intraventricular hemorrhage more than betamethasone [56]. Conversely, betamethasone may have more pronounced effects to suppress fetal movements and heart rate variation [46, 47]. Overall, there is a striking lack of information about the effects of these steroids on neural outcomes or fetal responses to hypoxia, and few formal comparisons have been performed.

6. The Effects of Glucocorticoids on Postnatal Hypoxic-Ischemic Brain Injury

The effect of glucocorticoids during and after HI in rodents appears to be rather variable. Clinically, glucocorticoids are used therapeutically to reduce brain edema, but clinical trials of glucocorticoids in ischemic stroke, intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and traumatic brain injury have not shown any clear therapeutic effect [57]. Experimental studies of ischemia in adult rats or in vitro have generally suggested increased injury when glucocorticoids are given before the insult (range 1 to 48 h beforehand) [58–65]. Immediate pretreatment was reported to have no effect, whereas chronic postinsult treatment reduced injury in the caudate nucleus, but had no effect on other brain areas [60].

In contrast, in newborn rats at postnatal day 7 (P7), when brain maturation is equivalent to the mildly preterm infant [66, 67], preinsult treatment (4 to 48 h beforehand) significantly reduced injury [68–74]. In contrast, glucocorticoids were not protective if given just before (0 to 3 h) or after HI [68, 75], and post-HI treatment increased mortality [75]. Antenatal treatment (on embryonic days 17, 18, and 19) has also been associated with reduced survival during hypoxia on the day after birth [76].

Injury may be mediated by reduced glucose uptake and energy utilization, accelerated ATP loss, and excessive Ca²⁺ mobilization during ischemia, and augmented excitotoxic and inflammatory responses post-ischemia [59, 61, 62, 77–80]. Conversely, neuroprotection has been related to stabilizing ATP production, with maintenance of glycolytic flux [70, 81, 82]. There may be maturation dependent responses to glucocorticoids, dependent in part on cerebral metabolism [83–85]. In support of this, preischemic hyperglycemia reduced injury in P7 rats due to energy preservation [86–88].

However, this may well be a species dependent response as hyperglycemia increased injury in newborn piglets, despite energy preservation [89]. Postischemic hyperglycemia was not protective in either species [90, 91]. In adult animals glucose can increase, reduce or have no impact on injury [58, 59, 92–99], and clinically it remains highly controversial whether controlling glucose affects outcomes after ischemia [100]. Nevertheless, maternal diabetes is associated with adverse neurodevelopmental outcomes in children, and this is strongly correlated with maternal hyperglycemia [101]. Further, hyperglycemia in preterm infants is associated with increased morbidity and mortality [102].

7. How Do Glucocorticoids Affect the Fetus?

Glucocorticoids are well documented to acutely affect fetal behaviour and cardiovascular function [103–106]. For example, a single clinical course of maternal dexamethasone in sheep at 0.7 of gestation, when brain development is broadly consistent with the 28 to 32 week human fetus [107], was associated with an acute, transient increase in mean arterial blood pressure with a rise in carotid and femoral vascular resistance, a fall in femoral arterial blood flow, and a brief fall in fetal heart rate followed by tachycardia (Figure 1) [106]. There was a persistent loss of the circadian pattern of fetal heart rate variability 3 days after maternal dexamethasone. Similarly, in pregnant sheep near-term, when fetal brain development is broadly comparable to the term human [107, 108], a clinical regime of betamethasone was associated with reduced fetal cerebral perfusion and increased cerebral metabolic activity [109]. In preterm fetal sheep, a clinical dose of maternal dexamethasone reduced the number and duration of interburst intervals [110], with a commensurate increase in the continuity of the fetal EEG, suggesting that glucocorticoid exposure increased the functional maturation of the brain (Figures 2 and 3). Other effects include the intriguing finding in near-term fetal sheep that exposure to dexamethasone increased Na-K-ATPase activity and tight junction expression [111, 112]. This may be of significance, since in neonatal rats, treatment with dexamethasone before HI was associated with both reduced blood brain barrier leakage and reduced HI brain injury at P7 and P14, but not P21 [103].

Figure 1

Time sequence of changes in mean arterial pressure (MAP), fetal heart rate (FHR), carotid blood flow (CaBF), and carotid vascular resistance (CaVR) in 0.7 gestation fetuses after two maternal intramuscular injections of either saline (open squares, ) or dexamethasone (filled squares, ). Dexamethasone induced a significant increase in MAP after each injection, and pressure was elevated for 50 hours. FHR fell acutely after each injection, and there was a sustained period of tachycardia after the second injection. There was a tendency for CaBF to fall initially, and this was associated with a significant rise in resistance. However, overall there were no marked differences in cerebral perfusion and resistance. Data are shown from six hours before the first injection to 120 hours afterwards. The dashed arrows show the timing of injections. Data are one hour averages, mean (SEM), *.

Figure 2

Time course changes in EEG power (dB, decibels) before and after two injections of dexamethasone (filled squares) or saline (open squares) 24 hours apart. The injections for each group are marked by dotted lines (DEX-1 and DEX-2). A significant increase in EEG power was seen after both DEX-1 and DEX-2, but the effects of DEX were most significant after the first injection. Peak amplitude changes were around 12 hours, and the increase in amplitude was mediated by an overall increase in normal sleep architecture waveforms and the appearance of seizures (see Figure 3). Data are one hour means ± SEM from six hours before until 120 hours after DEX-1.

(a)

(b)

(c)

Figure 3

Example of sleep state architecture in a 0.7 gestation preterm fetal lamb before exposure to maternal dexamethasone (panel (a)) and after dexamethasone (panel (b)). The normal sleep patterns of fetal sheep at this age is composed of mixed EEG amplitudes and frequencies, with mean amplitude typically around 60–70 μV. Transient waveforms (fast, sharp, and slow waves between 70–400 ms) are seen as part of this normal EEG patterns and their amplitude is typically between 70–150 μV. After dexamethasone exposure, there is a significant change in sleep architecture characterised by a significant increase in EEG amplitude (with background amplitudes increased to above 100 μV and spikes ranging between 200–600 μV), and a general reduction in high-frequency activity. Seizures and seizure-like activity is also observed and an example of this is shown in panel (c). While many of these seizures were high amplitude, it is notable that many were relatively low amplitude. All figures are raw data from one animal.

There are no data on whether glucocorticoid exposure may affect the preterm fetal ability to adapt to hypoxia. However, in near-term fetal sheep maternal dexamethasone (2 maternal injections 24 h apart) before moderate isocapnic hypoxia, which does not cause overt neural injury, was associated with impaired cardiovascular responses, with significant bradycardia and increased acidosis during hypoxia 8 hours after the second injection, whereas there was no effect 3 days after the second injection [113, 114]. Despite suppression of hypothalamic-pituitary axis function [115], low doses of dexamethasone augmented the glycemic response to hypoxia in near-term sheep fetuses [116].

8. The Effects of Glucocorticoids on Brain Activity in Preterm Fetal Sheep: A Potential Role for Conditioning?

We recently demonstrated that a clinical course of maternal dexamethasone was associated with significant dysregulation of brain activity in healthy preterm fetal sheep, including a loss of the normal gating of EEG waveform amplitude, and induction of seizures (Figures 2 and 3) [110]. In this paradigm, fetal blood glucose transiently increased, peaking ~4–6 h after maternal DEX treatment [106, 110]. There was no cerebral injury after 5 d of recovery. Seizures in early life in the rat [117], and other settings [118], can induce neuroprotection against later injury through preconditioning mechanisms, for example, by inducing protective gene changes. Thus, it is plausible that this activity could be beneficial given the serious neural risks of preterm birth [36].

The caveat to this reassuring hypothesis is that after exposure to preconditioning insults, such as seizures, it typically takes several days before protection is established [119–122]. If there are only a few hours between the stimulus and the HI insult, then sensitization occurs [119–122]. Thus, injury may occur with an otherwise noninjurious insult. In this setting both hyperglycemia and greater transient activity after glucocorticoid exposure could make the brain more vulnerable to HI. Epileptiform transients are associated with greater injury after HI in the preterm fetal sheep [123], likely by increasing the metabolic stress of injured cells making them vulnerable to further hypoxia [124]. Hyperglycemia increases glucose utilisation in the fetus [125], increasing neural metabolism and the metabolic demand on sick cells [126, 127]. Again, although these data are not definitive, they suggest potential for risk.

9. Glucocorticoids and HI in the Fetus

Rather remarkably, given the established clinical use of glucocorticoids for threatened premature delivery, we have been able to identify only one study of their effects on HI injury in the fetus. In near-term fetal sheep, Ellit and colleagues reported that chronic pretreatment (48 h before ischemia induced by carotid artery occlusion) had no effect on subsequent ischemic brain injury [128]. In contrast, in cultured embryonic rat basal forebrain cells, exposure to dexamethasone before oxygen-glucose deprivation was associated with increased injury [77]; this damage could be negated by glutamate receptor blockade. Potentially these contrasting results between protection in rats, no effect in sheep, and increased injury in vitro, might be related to species or to the specific model of brain injury, or to lower plasma levels after maternal treatment compared to direct neonatal injection. It is also critical to appreciate that the dose response for the glucocorticoid effects on neuronal cell viability and survival is both narrow and U-shaped [129].

10. Conclusions

Given the frighteningly limited information on whether glucocorticoids protect or sensitise to HI brain injury in preterm fetuses [130] it is of considerable concern that glucocorticoids have been suggested to be potential perinatal neuroprotection agents [84, 85]. The recent finding discussed above that a clinical course of maternal dexamethasone exposure triggers major changes in brain activity, including epileptiform events now raises the possibility that maternal glucocorticoids may well be both protective and damaging, depending on the precise timing before the preterm fetus and infant are exposed to an HI insult. These concepts suggest that as with so many aspects of neonatology timing is everything! [131] In turn, variations in timing of exposure may well explain the rather variable effects of maternal treatment in human clinical trials suggested above. Further systematic clinical and basic science studies are essential to tease out these factors.

Acknowledgments

This study was supported by the Health Research Council of New Zealand, The Auckland Medical Research Foundation, and the Lottery Grants Board of New Zealand.

References

G. C. Liggins and R. N. Howie, “A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants,” Pediatrics, vol. 50, no. 4, pp. 515–525, 1972.
View at: Google Scholar
L. C. Gilstrap, R. Christensen, W. H. Clewell et al., “Effect of corticosteroids for fetal maturation on perinatal outcomes,” Journal of the American Medical Association, vol. 273, no. 5, pp. 413–418, 1995.
View at: Google Scholar
D. Roberts and S. Dalziel, “Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth,” Cochrane Database of Systematic Reviews, vol. 3, Article ID CD004454, 2006.
View at: Google Scholar
O. Baud, L. Foix-L'Helias, M. Kaminski et al., “Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants,” New England Journal of Medicine, vol. 341, no. 16, pp. 1190–1196, 1999.
View at: Publisher Site | Google Scholar
A. Whitelaw and M. Thoresen, “Antenatal steroids and the developing brain,” Archives of Disease in Childhood, vol. 83, no. 2, pp. F154–F157, 2000.
View at: Google Scholar
I. Antonow-Schlorke, A. Helgert, and C. Gey et al., “Adverse effects of antenatal glucocorticoids on cerebral myelination in sheep,” Obstetrics & Gynecology, vol. 113, no. 1, pp. 142–151, 2009.
View at: Google Scholar
M. Schwab, I. Antonow-Schlorke, B. Kühn et al., “Effect of antenatal betamethasone treatment on microtubule-associated proteins MAP1B and MAP2 in fetal sheep,” Journal of Physiology, vol. 530, no. 3, pp. 497–506, 2001.
View at: Publisher Site | Google Scholar
I. Antonow-Schlorke, B. Kühn, T. Müller et al., “Antenatal betamethasone treatment reduces synaptophysin immunoreactivity in presynaptic terminals in the fetal sheep brain,” Neuroscience Letters, vol. 297, no. 3, pp. 147–150, 2001.
View at: Publisher Site | Google Scholar
I. Antonow-Schlorke, M. Schwab, C. Li, and P. W. Nathanielsz, “Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain,” Journal of Physiology, vol. 547, no. 1, pp. 117–123, 2003.
View at: Publisher Site | Google Scholar
S. A. Dunlop, M. A. Archer, J. A. Quinlivan, L. D. Beazley, and J. P. Newnham, “Repeated prenatal corticosteroids delay myelination in the ovine Central Nervous System,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 6, no. 6, pp. 309–313, 1997.
View at: Google Scholar
W. L. Huang, C. G. Harper, S. F. Evans, J. P. Newnham, and S. A. Dunlop, “Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep,” International Journal of Developmental Neuroscience, vol. 19, no. 4, pp. 415–425, 2001.
View at: Publisher Site | Google Scholar
A. Scheepens, M. van de Waarenbug, D. van den Hove, and C. E. Blanco, “A single course of prenatal betamethasone in the rat alters postnatal brain cell proliferation but not apoptosis,” Journal of Physiology, vol. 552, no. 1, pp. 163–175, 2003.
View at: Publisher Site | Google Scholar
M. Schwab, M. Roedel, M. Akhtar Anwar et al., “Effects of betamethasone administration to the fetal sheep in late gestation on fetal cerebral blood flow,” Journal of Physiology, vol. 528, no. 3, pp. 619–632, 2000.
View at: Google Scholar
M. Schwab, K. Schmidt, M. Roedel et al., “Non-linear changes of electrocortical activity after antenatal betamethasone treatment in fetal sheep,” Journal of Physiology, vol. 531, no. 2, pp. 535–543, 2001.
View at: Publisher Site | Google Scholar
W. L. Huang, L. D. Beazley, J. A. Quinlivan, S. F. Evans, J. P. Newnham, and S. A. Dunlop, “Effect of corticosteroids on brain growth in fetal sheep,” Obstetrics and Gynecology, vol. 94, no. 2, pp. 213–218, 1999.
View at: Publisher Site | Google Scholar
N. P. French, R. Hagan, S. F. Evans, A. Mullan, and J. P. Newnham, “Repeated antenatal corticosteroids: effects on cerebral palsy and childhood behavior,” American Journal of Obstetrics and Gynecology, vol. 190, no. 3, pp. 588–595, 2004.
View at: Publisher Site | Google Scholar
B. A. MacArthur, R. N. Howie, J. A. Dezoete, and J. Elkins, “Cognitive and psychosocial development of 4-year-old children whose mothers were treated antenatally with betamethasone,” Pediatrics, vol. 68, no. 5, pp. 638–643, 1981.
View at: Google Scholar
B. A. MacArthur, R. N. Howie, J. A. Dezoete, and J. Elkins, “School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone,” Pediatrics, vol. 70, no. 1, pp. 99–105, 1982.
View at: Google Scholar
H. Smolders-De Haas, J. Neuvel, B. Schmand, P. E. Treffers, J. G. Koppe, and J. Hoeks, “Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up,” Pediatrics, vol. 86, no. 1, pp. 65–70, 1990.
View at: Google Scholar
D. J. Murphy, “Effect of antenatal corticosteroids on postmortem brain weight of preterm babies,” Early Human Development, vol. 63, no. 2, pp. 113–122, 2001.
View at: Publisher Site | Google Scholar
E. W. Y. Tam, V. Chau, D. M. Ferriero et al., “Preterm birth: preterm cerebellar growth impairment after postnatal exposure to glucocorticoids,” Science Translational Medicine, vol. 3, no. 105, p. 105ra105, 2011.
View at: Publisher Site | Google Scholar
O. Baud and A. Sola, “Corticosteroids in perinatal medicine: how to improve outcomes without affecting the developing brain?” Seminars in Fetal and Neonatal Medicine, vol. 12, no. 4, pp. 273–279, 2007.
View at: Publisher Site | Google Scholar
E. S. Shinwell and S. Eventov-Friedman, “Impact of perinatal corticosteroids on neuromotor development and outcome: review of the literature and new meta-analysis,” Seminars in Fetal and Neonatal Medicine, vol. 14, no. 3, pp. 164–170, 2009.
View at: Publisher Site | Google Scholar
N. Modi, H. Lewis, N. Al-Naqeeb, M. Ajayi-Obe, C. J. Dore, and M. Rutherford, “The effects of repeated antenatal glucocorticoid therapy on the developing brain,” Pediatric Research, vol. 50, no. 5, pp. 581–585, 2001.
View at: Google Scholar
A. Ali Khan, A. Rodriguez, M. Kaakinen, A. Pouta, A. L. Hartikainen, and M. R. Jarvelin, “Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? A systematic review of current evidence in humans,” Paediatric and Perinatal Epidemiology, vol. 25, no. 1, pp. 20–36, 2011.
View at: Publisher Site | Google Scholar
P. Leao, J. C. Sousa, M. Oliveira, R. Silva, O. F. X. Almeida, and N. Sousa, “Programming effects of antenatal dexamethasone in the developing mesolimbic pathways,” Synapse, vol. 61, no. 1, pp. 40–49, 2007.
View at: Publisher Site | Google Scholar
H. Uno, L. Lohmiller, C. Thieme et al., “Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques—I. Hippocampus,” Developmental Brain Research, vol. 53, no. 2, pp. 157–167, 1990.
View at: Publisher Site | Google Scholar
C. W. Noorlander, G. H. A. Visser, G. M. J. Ramakers, P. G. J. Nikkels, and P. N. E. De Graan, “Prenatal corticosteroid exposure affects hippocampal plasticity and reduces lifespan,” Developmental Neurobiology, vol. 68, no. 2, pp. 237–246, 2008.
View at: Publisher Site | Google Scholar
D. G. Zuloaga, D. L. Carbone, R. Hiroi, D. L. Chong, and R. J. Handa, “Dexamethasone induces apoptosis in the developing rat amygdala in an age-, region-, and sex-specific manner,” Neuroscience, vol. 199, pp. 535–547, 2011.
View at: Publisher Site | Google Scholar
K. K. Noguchi, K. C. Walls, D. F. Wozniak, J. W. Olney, K. A. Roth, and N. B. Farber, “Acute neonatal glucocorticoid exposure produces selective and rapid cerebellar neural progenitor cell apoptotic death,” Cell Death and Differentiation, vol. 15, no. 10, pp. 1582–1592, 2008.
View at: Publisher Site | Google Scholar
S. Yu, A. V. Patchev, Y. Wu et al., “Depletion of the neural precursor cell pool by glucocorticoids,” Annals of Neurology, vol. 67, no. 1, pp. 21–30, 2010.
View at: Publisher Site | Google Scholar
S. K. Damsted, A. P. Born, O. B. Paulson, and P. Uldall, “Exogenous glucocorticoids and adverse cerebral effects in children,” European Journal of Paediatric Neurology, vol. 15, no. 6, pp. 465–477, 2011.
View at: Publisher Site | Google Scholar
H. L. Halliday, R. A. Ehrenkranz, and L. W. Doyle, “Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD001145, 2009.
View at: Google Scholar
Committee on Understanding Premature Birth and Assuring Healthy Outcomes, “Preterm Birth: Causes, Consequences, and Prevention,” R. E. Behrman and A. S. Butler, Eds., Institute of Medicine, The National Academies Press, 2007, http://books.nap.edu//catalog/11622.html#toc.
View at: Google Scholar
Centers for Disease Control and Prevention (CDC), “Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment—United States, 2003,” Morbidity and Mortality Weekly Report, vol. 53, no. 3, pp. 57–59, 2004.
View at: Google Scholar
Committee on Understanding Premature Birth and Assuring Healthy Outcomes, “Preterm Birth: Causes, Consequences, and Prevention,” R. E. Behrman and A. S. Butler, Eds., Institute of Medicine of the National Academies, Washington, DC, USA, 2005.
View at: Google Scholar
D. Wilson-Costello, H. Friedman, N. Minich, A. A. Fanaroff, and M. Hack, “Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s,” Pediatrics, vol. 115, no. 4, pp. 997–1003, 2005.
View at: Publisher Site | Google Scholar
L. J. Woodward, P. J. Anderson, N. C. Austin, K. Howard, and T. E. Inder, “Neonatal MRI to predict neurodevelopmental outcomes in preterm infants,” New England Journal of Medicine, vol. 355, no. 7, pp. 685–694, 2006.
View at: Publisher Site | Google Scholar
S. Saigal and L. W. Doyle, “An overview of mortality and sequelae of preterm birth from infancy to adulthood,” The Lancet, vol. 371, no. 9608, pp. 261–269, 2008.
View at: Publisher Site | Google Scholar
S. E. G. Hamrick, S. P. Miller, C. Leonard et al., “Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia,” Journal of Pediatrics, vol. 145, no. 5, pp. 593–599, 2004.
View at: Publisher Site | Google Scholar
B. S. Peterson, B. Vohr, L. H. Staib et al., “Regional brain volume abnormalities and long-term cognitive outcome in preterm infants,” Journal of the American Medical Association, vol. 284, no. 15, pp. 1939–1947, 2000.
View at: Google Scholar
C. K. Shapiro-Mendoza, K. M. Tomashek, M. Kotelchuck et al., “Effect of late-preterm birth and maternal medical conditions on newborn morbidity risk,” Pediatrics, vol. 121, no. 2, pp. e223–e232, 2008.
View at: Publisher Site | Google Scholar
S. S. Billiards, C. R. Pierson, R. L. Haynes, R. D. Folkerth, and H. C. Kinney, “Is the late preterm infant more vulnerable to gray matter injury than the term infant?” Clinics in Perinatology, vol. 33, no. 4, pp. 915–933, 2006.
View at: Publisher Site | Google Scholar
I. S. Baron, K. Erickson, M. D. Ahronovich, R. Baker, and F. R. Litman, “Cognitive deficit in preschoolers born late-preterm,” Early Human Development, vol. 87, no. 2, pp. 115–119, 2011.
View at: Publisher Site | Google Scholar
M. A. Woythaler, M. C. McCormick, and V. C. Smith, “Late preterm infants have worse 24-month neurodevelopmental outcomes than term infants,” Pediatrics, vol. 127, no. 3, pp. e622–e629, 2011.
View at: Publisher Site | Google Scholar
J. A. Low, “Reflections on the occurrence and significance of antepartum fetal asphyxia,” Best Practice and Research, vol. 18, no. 3, pp. 375–382, 2004.
View at: Publisher Site | Google Scholar
R. D. Barrett, L. Bennet, J. Davidson et al., “Destruction and reconstruction: hypoxia and the developing brain,” Birth Defects Research Part C, vol. 81, no. 3, pp. 163–176, 2007.
View at: Publisher Site | Google Scholar
X. Wang, H. Hagberg, C. Nie, C. Zhu, T. Ikeda, and C. Mallard, “Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia,” Journal of Neuropathology and Experimental Neurology, vol. 66, no. 6, pp. 552–561, 2007.
View at: Publisher Site | Google Scholar
S. Eklind, C. Mallard, A. L. Leverin et al., “Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury,” European Journal of Neuroscience, vol. 13, no. 6, pp. 1101–1106, 2001.
View at: Publisher Site | Google Scholar
A. Larouche, M. Roy, H. Kadhim, A. M. Tsanaclis, D. Fortin, and G. Sébire, “Neuronal injuries induced by perinatal hypoxic-ischemic insults are potentiated by prenatal exposure to lipopolysaccharide: animal model for perinatally acquired encephalopathy,” Developmental Neuroscience, vol. 27, no. 2–4, pp. 134–142, 2005.
View at: Publisher Site | Google Scholar
B. J. Stoll, N. I. Hansen, I. Adams-Chapman et al., “Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection,” Journal of the American Medical Association, vol. 292, no. 19, pp. 2357–2365, 2004.
View at: Publisher Site | Google Scholar
J. A. Low, H. Killen, and E. J. Derrick, “Antepartum fetal asphyxia in the preterm pregnancy,” American Journal of Obstetrics and Gynecology, vol. 188, no. 2, pp. 461–465, 2003.
View at: Publisher Site | Google Scholar
B. H. Lee, B. J. Stoll, S. A. McDonald, and R. D. Higgins, “Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone,” Pediatrics, vol. 117, no. 5, pp. 1503–1510, 2006.
View at: Publisher Site | Google Scholar
B. H. Lee, B. J. Stoll, S. A. McDonald, and R. D. Higgins, “Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone,” Pediatrics, vol. 121, no. 2, pp. 289–296, 2008.
View at: Publisher Site | Google Scholar
M. R. R. Bar-Lev, A. Maayan-Metzger, I. Matok, Z. Heyman, E. Sivan, and J. Kuint, “Short-term outcomes in low birth weight infants following antenatal exposure to betamethasone versus dexamethasone,” Obstetrics and Gynecology, vol. 104, no. 3, pp. 484–488, 2004.
View at: Publisher Site | Google Scholar
A. Elimian, D. Garry, R. Figueroa, A. Spitzer, V. Wiencek, and J. G. Quirk, “Antenatal betamethasone compared with dexamethasone (Betacode trial): a randomized controlled trial,” Obstetrics and Gynecology, vol. 110, no. 1, pp. 26–30, 2007.
View at: Publisher Site | Google Scholar
P. A. Sandercock and T. Soane, “Corticosteroids for acute ischaemic stroke,” Cochrane Database of Systematic Reviews, vol. 9, Article ID CD000064, 2011.
View at: Google Scholar
V. L. Smith-Swintosky, L. C. Pettigrew, R. M. Sapolsky et al., “Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 4, pp. 585–598, 1996.
View at: Google Scholar
R. M. Sapolsky and W. A. Pulsinelli, “Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications,” Science, vol. 229, no. 4720, pp. 1397–1400, 1985.
View at: Google Scholar
T. Koide, T. W. Wieloch, and B. K. Siesjo, “Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis,” Journal of Cerebral Blood Flow and Metabolism, vol. 6, no. 4, pp. 395–404, 1986.
View at: Google Scholar
R. M. Sapolsky, “Glucocorticoids, hippocampal damage and the glutamatergic synapse,” Progress in Brain Research, vol. 86, pp. 13–23, 1990.
View at: Google Scholar
N. Adachi, J. Chen, K. Liu, S. Tsubota, and T. Arai, “Dexamethasone aggravates ischemia-induced neuronal damage by facilitating the onset of anoxic depolarization and the increase in the intracellular Ca2+ concentration in gerbil hippocampus,” Journal of Cerebral Blood Flow and Metabolism, vol. 18, no. 3, pp. 274–280, 1998.
View at: Google Scholar
N. Adachi, C. Namba, T. Nagaro, and T. Arai, “Dexamethasone reduces energy utilization in ischemic gerbil brain,” European Journal of Pharmacology, vol. 427, no. 2, pp. 119–123, 2001.
View at: Publisher Site | Google Scholar
S. Tsubota, N. Adachi, J. Chen, T. Yorozuya, T. Nagaro, and T. Arai, “Dexamethasone changes brain monoamine metabolism and aggravates ischemic neuronal damage in rats,” Anesthesiology, vol. 90, no. 2, pp. 515–523, 1999.
View at: Publisher Site | Google Scholar
M. Y. Cheng, G. Sun, M. Jin, H. Zhao, G. K. Steinberg, and R. M. Sapolsky, “Blocking glucocorticoid and enhancing estrogenic genomic signaling protects against cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 1, pp. 130–136, 2009.
View at: Publisher Site | Google Scholar
H. J. Romijn, M. A. Hofman, and A. Gramsbergen, “At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby?” Early Human Development, vol. 26, no. 1, pp. 61–67, 1991.
View at: Publisher Site | Google Scholar
J. M. Dean, M. D. Moravec, M. Grafe et al., “Strain-specific differences in perinatal rodent oligodendrocyte lineage progression and its correlation with human,” Developmental Neuroscience, vol. 33, no. 3-4, pp. 251–260, 2011.
View at: Publisher Site | Google Scholar
J. D. E. Barks, M. Post, and U. I. Tuor, “Dexamethasone prevents hypoxic-ischemic brain damage in the neonatal rat,” Pediatric Research, vol. 29, no. 6, pp. 558–563, 1991.
View at: Google Scholar
Y. Feng, P. G. Rhodes, and A. J. Bhatt, “Dexamethasone pre-treatment protects brain against hypoxic-ischemic injury partially through up-regulation of vascular endothelial growth factor A in neonatal rats,” Neuroscience, vol. 179, pp. 223–232, 2011.
View at: Publisher Site | Google Scholar
B. J. Dardzinski, S. L. Smith, J. Towfighi, G. D. Williams, R. C. Vannucci, and M. B. Smith, “Increased plasma beta-hydroxybutyrate, preserved cerebral energy metabolism, and amelioration of brain damage during neonatal hypoxia ischemia with dexamethasone pretreatment,” Pediatric Research, vol. 48, no. 2, pp. 248–255, 2000.
View at: Google Scholar
P. D. Chumas, M. R. Del Bigio, J. M. Drake, and U. I. Tuor, “A comparison of the protective effect of dexamethasone to other potential prophylactic agents in a neonatal rat model of cerebral hypoxia-ischemia,” Journal of Neurosurgery, vol. 79, no. 3, pp. 414–420, 1993.
View at: Google Scholar
T. Ikeda, K. Mishima, N. Aoo et al., “Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats,” American Journal of Obstetrics and Gynecology, vol. 192, no. 3, pp. 719–726, 2005.
View at: Publisher Site | Google Scholar
K. Felszeghy, G. Banisadr, W. Rostène, C. Nyakas, and F. Haour, “Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats,” NeuroImmunoModulation, vol. 11, no. 6, pp. 404–413, 2004.
View at: Publisher Site | Google Scholar
P. Ekert, N. MacLusky, X. P. Luo et al., “Dexamethasone prevents apoptosis in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE) by a reactive oxygen species-independent mechanism,” Brain Research, vol. 747, no. 1, pp. 9–17, 1997.
View at: Publisher Site | Google Scholar
D. I. Altman, R. S. K. Young, and S. K. Yagel, “Effects of dexamethasone in hypoxic-ischemic brain injury in the neonatal rat,” Biology of the Neonate, vol. 46, no. 3, pp. 149–156, 1984.
View at: Google Scholar
K. S. Kauffman, F. J. Seidler, and T. A. Slotkin, “Prenatal dexamethasone exposure causes loss of neonatal hypoxia tolerance: cellular mechanisms,” Pediatric Research, vol. 35, no. 5, pp. 515–522, 1994.
View at: Google Scholar
M. P. Flavin, “Influence of dexamethasone on neurotoxicity caused by oxygen and glucose deprivation in vitro,” Experimental Neurology, vol. 139, no. 1, pp. 34–38, 1996.
View at: Publisher Site | Google Scholar
S. F. Sorrells, J. R. Caso, C. D. Munhoz, and R. M. Sapolsky, “The stressed CNS: when glucocorticoids aggravate inflammation,” Neuron, vol. 64, no. 1, pp. 33–39, 2009.
View at: Publisher Site | Google Scholar
M. Kadekaro, M. Ito, and P. M. Gross, “Local cerebral glucose utilization is increased in acutely adrenalectomized rats,” Neuroendocrinology, vol. 47, no. 4, pp. 329–334, 1988.
View at: Google Scholar
H. C. Horner, D. R. Packan, and R. M. Sapolsky, “Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia,” Neuroendocrinology, vol. 52, no. 1, pp. 57–64, 1990.
View at: Google Scholar
U. I. Tuor, J. Y. Yager, S. Bascaramurty, and M. R. Del Bigio, “Dexamethasone prevents hypoxia/ischemia-induced reductions in cerebral glucose utilization and high-energy phosphate metabolites in immature brain,” Journal of Neurochemistry, vol. 69, no. 5, pp. 1954–1963, 1997.
View at: Google Scholar
R. C. Vannucci, R. M. Brucklacher, and S. J. Vannucci, “Glycolysis and perinatal hypoxic-ischemic brain damage,” Developmental Neuroscience, vol. 27, no. 2–4, pp. 185–190, 2005.
View at: Publisher Site | Google Scholar
R. C. Vannucci and S. J. Vannucci, “Glucose metabolism in the developing brain,” Seminars in Perinatology, vol. 24, no. 2, pp. 107–115, 2000.
View at: Google Scholar
U. I. Tuor, “Glucocorticoids and the prevention of hypoxic-ischemic brain damage,” Neuroscience and Biobehavioral Reviews, vol. 21, no. 2, pp. 175–179, 1997.
View at: Publisher Site | Google Scholar
J. M. Perlman, “Antenatal glucocorticoid, magnesium exposure, and the prevention of brain injury of prematurity,” Seminars in Pediatric Neurology, vol. 5, no. 3, pp. 202–210, 1998.
View at: Publisher Site | Google Scholar
T. M. Voorhies, D. Rawlinson, and R. C. Vannucci, “Glucose and perinatal hypoxic-ischemic brain damage in the rat,” Neurology, vol. 36, no. 8, pp. 1115–1118, 1986.
View at: Google Scholar
R. C. Vannucci, “Cerebral carbohydrate and energy metabolism in perinatal hypoxic-ischemic brain damage,” Brain Pathology, vol. 2, no. 3, pp. 229–234, 1992.
View at: Google Scholar
R. C. Vannucci and D. J. Mujsce, “Effect of glucose on perinatal hypoxic-ischemic brain damage,” Biology of the Neonate, vol. 62, no. 4, pp. 215–224, 1992.
View at: Google Scholar
M. H. LeBlanc, M. Huang, V. Vig, D. Patel, E. E. Smith, and D. W. Busija, “Glucose affects the severity of hypoxic-ischemic brain injury in newborn pigs,” Stroke, vol. 24, no. 7, pp. 1055–1062, 1993.
View at: Google Scholar
R. A. Sheldon, J. C. Partridge, and D. M. Ferriero, “Postischemic hyperglycemia is not protective to the neonatal rat brain,” Pediatric Research, vol. 32, no. 4, pp. 489–493, 1992.
View at: Google Scholar
M. H. LeBlanc, M. Huang, D. Patel, E. E. Smith, and M. Devidas, “Glucose given after hypoxic ischemia does not affect brain injury in piglets,” Stroke, vol. 25, no. 7, pp. 1443–1448, 1994.
View at: Google Scholar
M. Nedergaard, R. P. Kraig, J. Tanabe, and W. A. Pulsinelli, “Dynamics of interstitial and intracellular pH in evolving brain infarct,” American Journal of Physiology, vol. 260, no. 3, pp. R581–R588, 1991.
View at: Google Scholar
A. Schurr, “Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia,” Critical Care, vol. 6, no. 4, pp. 330–334, 2002.
View at: Google Scholar
M. Nedergaard, A. Gjedde, and N. H. Diemer, “Hyperglycaemia protects against neuronal injury around experimental brain infarcts,” Neurological Research, vol. 9, no. 4, pp. 241–244, 1987.
View at: Google Scholar
S. Y. Seo, E. Y. Kim, H. Kim, I. Jou, and B. J. Gwag, “Attenuation of neuronal death by NMDA and oxygen-glucose deprivation in cortical neurons maintained in high glucose,” Annals of the New York Academy of Sciences, vol. 893, pp. 396–399, 1999.
View at: Google Scholar
G. F. Tian and A. J. Baker, “Glycolysis prevents anoxia-induced synaptic transmission damage in rat hippocampal slices,” Journal of Neurophysiology, vol. 83, no. 4, pp. 1830–1839, 2000.
View at: Google Scholar
M. D. Ginsbery, R. Prado, and W. D. Dietrich, “Hyperglycemia reduces the extent of cerebral infarction in rats,” Stroke, vol. 18, no. 3, pp. 570–574, 1987.
View at: Google Scholar
M. A. Zasslow, R. G. Pearl, L. M. Shuer, G. K. Steinberg, R. E. Lieberson, and C. P. Larson, “Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats,” Stroke, vol. 20, no. 4, pp. 519–523, 1989.
View at: Google Scholar
U. I. Tuor and M. R. Del Bigio, “Protection against hypoxic-ischemic damage with corticosterone and dexamethasone: inhibition of effect by a glucocorticoid antagonist, RU38486,” Brain Research, vol. 743, no. 1-2, pp. 258–262, 1996.
View at: Publisher Site | Google Scholar
S. Mehta, “The glucose paradox of cerebral ischaemia,” Journal of Postgraduate Medicine, vol. 49, no. 4, pp. 299–301, 2003.
View at: Google Scholar
A. Ornoy, “Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes,” Pediatric Endocrinology Reviews, vol. 3, no. 2, pp. 104–113, 2005.
View at: Google Scholar
A. L. Ogilvy-Stuart and K. Beardsall, “Management of hyperglycaemia in the preterm infant,” Archives of Disease in Childhood, vol. 95, no. 2, pp. F126–F131, 2010.
View at: Publisher Site | Google Scholar
E. J. H. Mulder, R. de Heus, and G. H. A. Visser, “Antenatal corticosteroid therapy: short-term effects on fetal behaviour and haemodynamics,” Seminars in Fetal and Neonatal Medicine, vol. 14, no. 3, pp. 151–156, 2009.
View at: Publisher Site | Google Scholar
E. J. H. Mulder, J. B. Derks, and G. H. A. Visser, “Antenatal corticosteroid therapy and fetal behaviour: a randomised study of the effects of betamethasone and dexamethasone,” British Journal of Obstetrics and Gynaecology, vol. 104, no. 11, pp. 1239–1247, 1997.
View at: Google Scholar
L. Bennet, S. Kozuma, H. H. G. McGarrigle, and M. A. Hanson, “Temporal changes in fetal cardiovascular, behavioural, metabolic and endocrine responses to maternally administered dexamethasone in the late gestation fetal sheep,” British Journal of Obstetrics and Gynaecology, vol. 106, no. 4, pp. 331–339, 1999.
View at: Google Scholar
J. S. Quaedackers, V. Roelfsema, M. Fraser, A. J. Gunn, and L. Bennet, “Cardiovascular and endocrine effects of a single course of maternal dexamethasone treatment in preterm fetal sheep,” British Journal of Obstetrics and Gynaecology, vol. 112, no. 2, pp. 182–191, 2005.
View at: Publisher Site | Google Scholar
R. M. Barlow, “The foetal sheep: morphogenesis of the nervous system and histochemical aspects of myelination,” Journal of Comparative Neurology, vol. 135, no. 3, pp. 249–262, 1969.
View at: Google Scholar
G. H. McIntosh, K. I. Baghurst, B. J. Potter, and B. S. Hetzel, “Foetal brain development in the sheep,” Neuropathology and Applied Neurobiology, vol. 5, no. 2, pp. 103–114, 1979.
View at: Google Scholar
J. McCallum, N. Smith, M. Schwab et al., “Effects of antenatal glucocorticoids on cerebral substrate metabolism in the preterm ovine fetus,” American Journal of Obstetrics and Gynecology, vol. 198, no. 1, pp. e101–e109, 2008.
View at: Publisher Site | Google Scholar
J. O. Davidson, J. S. L. T. Quaedackers, S. A. George, A. J. Gunn, and L. Bennet, “Maternal dexamethasone and EEG hyperactivity in preterm fetal sheep,” Journal of Physiology, vol. 589, no. 15, pp. 3823–3835, 2011.
View at: Publisher Site | Google Scholar
N. S. Mehter, G. B. Sadowska, S. N. Malaeb, and B. S. Stonestreet, “Na+, K+-ATPase activity and subunit isoform protein abundance: effects of antenatal glucocorticoids in the frontal cerebral cortex and renal cortex of ovine fetuses,” Reproductive Sciences, vol. 16, no. 3, pp. 294–307, 2009.
View at: Publisher Site | Google Scholar
G. B. Sadowska, S. N. Malaeb, and B. S. Stonestreet, “Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep,” American Journal of Physiology, vol. 298, no. 1, pp. H179–H188, 2010.
View at: Publisher Site | Google Scholar
J. K. Jellyman, D. S. Gardner, C. M. B. Edwards, A. L. Fowden, and D. A. Giussani, “Fetal cardiovascular, metabolic and endocrine responses to acute hypoxaemia during and following maternal treatment with dexamethasone in sheep,” Journal of Physiology, vol. 567, no. 2, pp. 673–688, 2005.
View at: Publisher Site | Google Scholar
A. J. W. Fletcher, D. S. Gardner, C. M. B. Edwards, A. B. Fowden, and D. A. Giussani, “Cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in the ovine fetus,” Journal of Physiology, vol. 549, no. 1, pp. 271–287, 2003.
View at: Publisher Site | Google Scholar
J. K. Jellyman, D. S. Gardner, H. H. G. McGarrigle, A. L. Fowden, and D. A. Giussani, “Pituitary-adrenal responses to acute hypoxemia during and after maternal dexamethasone treatment in sheep,” Pediatric Research, vol. 56, no. 6, pp. 864–872, 2004.
View at: Publisher Site | Google Scholar
A. J. W. Fletcher, M. R. Goodfellow, A. J. Forhead et al., “Low doses of dexamethasone suppress pituitary-adrenal function but augment the glycemic response to acute hypoxemia in fetal sheep during late gestation,” Pediatric Research, vol. 47, no. 5, pp. 684–691, 2000.
View at: Google Scholar
A. Saghyan, G. N. LaTorre, R. Keesey et al., “Glutamatergic and morphological alterations associated with early life seizure-induced preconditioning in young rats,” European Journal of Neuroscience, vol. 32, no. 11, pp. 1897–1911, 2010.
View at: Publisher Site | Google Scholar
E. M. Jimenez-Mateos and D. C. Henshall, “Seizure preconditioning and epileptic tolerance: models and mechanisms,” International Journal of Physiology, Pathophysiology and Pharmacology, vol. 1, no. 2, pp. 180–191, 2009.
View at: Google Scholar
U. Dirnagl, K. Becker, and A. Meisel, “Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use,” The Lancet Neurology, vol. 8, no. 4, pp. 398–412, 2009.
View at: Publisher Site | Google Scholar
U. Dirnagl and A. Meisel, “Endogenous neuroprotection: mitochondria as gateways to cerebral preconditioning?” Neuropharmacology, vol. 55, no. 3, pp. 334–344, 2008.
View at: Publisher Site | Google Scholar
R. D. Sanders, H. J. Manning, N. J. Robertson et al., “Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term,” Anesthesiology, vol. 113, no. 1, pp. 233–249, 2010.
View at: Publisher Site | Google Scholar
H. Hagberg, P. Gressens, and C. Mallard, “Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults,” JAnnals of Neurology, vol. 71, no. 4, pp. 444–457, 2012.
View at: Google Scholar
L. Bennet, L. Booth, and A. J. Gunn, “Potential biomarkers for hypoxic-ischemic encephalopathy,” Seminars in Fetal and Neonatal Medicine, vol. 15, no. 5, pp. 253–260, 2010.
View at: Publisher Site | Google Scholar
W. R. Selman, W. D. Lust, S. Pundik, Y. Zhou, and R. A. Ratcheson, “Compromised metabolic recovery following spontaneous spreading depression in the penumbra,” Brain Research, vol. 999, no. 2, pp. 167–174, 2004.
View at: Publisher Site | Google Scholar
W. W. Hay Jr., S. A. Myers, and J. W. Sparks, “Glucose and lactate oxidation rates in the fetal lamb,” Proceedings of the Society for Experimental Biology and Medicine, vol. 173, no. 4, pp. 553–563, 1983.
View at: Google Scholar
R. G. Shulman, F. Hyder, and D. L. Rothman, “Cerebral energetics and the glycogen shunt: neurochemical basis of functional imaging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 11, pp. 6417–6422, 2001.
View at: Publisher Site | Google Scholar
Z. Wang, W. Luo, P. Li, J. Qiu, and Q. Luo, “Acute hyperglycemia compromises cerebral blood flow following cortical spreading depression in rats monitored by laser speckle imaging,” Journal of Biomedical Optics, vol. 13, no. 6, Article ID 064023, 2008.
View at: Publisher Site | Google Scholar
C. M. Elitt, G. B. Sadowska, E. G. Stopa, H. Pinar, K. H. Petersson, and B. S. Stonestreet, “Effects of antenatal steroids on ischemic brain injury in near-term ovine fetuses,” Early Human Development, vol. 73, no. 1-2, pp. 1–15, 2003.
View at: Publisher Site | Google Scholar
I. M. Abraham, P. Meerlo, and P. G. Luiten, “Concentration dependent actions of glucocorticoids on neuronal viability and survival,” Dose-Response, vol. 4, pp. 38–54, 2006.
View at: Google Scholar
W. D. Lust, S. Pundik, J. Zechel, Y. Zhou, M. Buczek, and W. R. Selman, “Changing metabolic and energy profiles in fetal, neonatal, and adult rat brain,” Metabolic Brain Disease, vol. 18, no. 3, pp. 195–206, 2003.
View at: Publisher Site | Google Scholar
A. J. Gunn and L. Bennet, “Hypothermia in the management of hypoxic-ischemic encephalopathy,” NeoReviews, vol. 3, pp. e116–e122, 2002.
View at: Google Scholar

Copyright

Copyright © 2012 Laura Bennet et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3272

Downloads

1597

Citations