Pathophysiology of neonatal brain lesions: Lessons from animal models of excitotoxicity

Mesples, Bettina; Plaisant, Frank; Fontaine, R; Gressèns, Pierre

doi:10.1080/08035250410022378

Cited by 49 publications

(14 citation statements)

References 35 publications

(43 reference statements)

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“…However, excessive activation of microglia and the consequent production of pro-inflammatory cytokines are believed to be neurotoxic and microglia activation has been demonstrated in association with experimental studies of neonatal brain damage (21)(22)(23)). An increase in the expression of TNF-␣ was also found in brain autopsies from infants with PVL and these cytokines were mainly expressed by microglia cells and hypertrophic astrocytes (24).…”

Section: Discussionmentioning

confidence: 99%

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

et al. 2007

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ABSTRACT:The premature infant is at increased risk of cerebral white matter injury. Melatonin is neuroprotective in adult models of focal cerebral ischemia and attenuates ibotenate-induced white matter cysts in neonatal mice. Clinically, melatonin has been used to treat sleep disorders in children without major side effects. The aim of this study was to investigate the protective and anti-inflammatory effects of melatonin in the immature brain following intrauterine asphyxia. Fetal sheep at 90 d of gestation were subjected to umbilical cord occlusion. Melatonin (20 mg/kg, n ϭ 9) or vehicle (n ϭ 10) was administered IV to the fetus, starting 10 min after the start of reperfusion and continued for 6 h. Melatonin treatment resulted in a slower recovery of fetal blood pressure following umbilical cord occlusion, but without changes in fetal heart rate, acid base status or mortality. The production of 8-isoprostanes following umbilical cord occlusion was attenuated and there was a reduction in the number of activated microglia cells and TUNEL-positive cells in melatonin treated fetuses, suggesting a protective effect of melatonin. In conclusion, this study shows that melatonin attenuates cell death in the fetal brain in association with a reduced inflammatory response in the blood and the brain following intrauterine asphyxia in mid-gestation fetal sheep. T he premature infant is at increased risk of cerebral white matter injury, often referred to as periventricular leukomalacia (PVL), which is associated with subsequent development of cerebral palsy and cognitive impairment (1,2). The precise etiology of white matter damage remains unclear, but ischemia-reperfusion and generation of free radicals seem to play an important role (3). Presently, there are no effective treatments for preterm brain injury, although encouraging studies suggest that hypothermic treatment in term infants following birth asphyxia is successful in reducing mortality/ morbidity (4,5).Melatonin is the major secretory product of the pineal gland and its main physiologic function is to mediate circadian rhythmicity and seasonality (6). Clinically, melatonin has been used to treat sleep disorders in children and jet-lag (7,8) and melatonin administered to neonates reduced oxidative stress in association with septicaemia (9). Furthermore, treatment with melatonin in asphyxiated newborns reduced levels of malondialdehyde and nitrite/nitrate in the blood (10).In adult animals, melatonin has been shown to be neuroprotective in models of focal cerebral ischemia (11) and to reduce microglia activation in the hippocampus after kainateinduced inflammation in rats (12). Melatonin also attenuated ibotenate-induced white matter cysts in neonatal mice (13). In addition, melatonin given to pregnant rats prevented oxidative mitochondria damage after ischemia-reperfusion in premature fetal rat brain (14).We have previously demonstrated white matter injury following systemic asphyxia in the preterm fetal sheep, which is similar to the injury seen in preterm infan...

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Section: Discussionmentioning

confidence: 99%

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

et al. 2007

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“…However, CUMS effects were present in both white matter and gray matter lesions when induced by an NMDA receptor agonist (ibotenate or NMDA), whereas this deleterious effect was observed only in white matter lesions induced by an AMPA-kainate receptor agonist (Sbromowillardiine). These differential effects of CUMS might be a result of the molecular mechanisms by which CUMS induces an increased vulnerability to neonatal excitotoxic lesions (see below) and/or of the specific cellular and molecular mechanisms by which these glutamatergic analogs damage the gray and white matters in the newborn brain (Tahraoui et al, 2001;Mesples et al, 2005;Sfaello et al, 2005). The fact that CUMS increased NMDA receptor binding sites could explain the specificity (see below).…”

Section: Cums Is a Factor Of Vulnerability To Neonatal Excitotoxic Brmentioning

confidence: 99%

Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

Rangon

Fortes²,

Lelièvre³

et al. 2007

J. Neurosci.

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Cerebral palsy remains a public health priority. Recognition of factors of susceptibility to perinatal brain lesions is key for the prevention of cerebral palsy. In most cases, the pathophysiology of these lesions is thought to involve prior exposure to predisposing factors that make the developing brain more vulnerable to perinatal events. The present study tested the hypothesis that exposure to chronic minimal stress throughout gestation would sensitize the offspring to neonatal excitotoxic brain lesions, which mimic lesions observed in cerebral palsy. Pregnant mice were exposed to chronic, ultramild stress, applied throughout gestation. Neonatal brain lesions were induced by intracerebral injection of glutamate analogs. Excitotoxic lesions were significantly worsened in pups exposed to gestational stress. Stress induced a significant rise of circulating corticosterone levels both in pregnant mothers and in newborn pups. The deleterious effects of stress on excitotoxicity were totally suppressed in mice with reduced levels of glucocorticoid receptors. Stress induced a significant increase of neopallial NMDA binding sites in the offspring. At adulthood, animals exposed to stress and neonatal excitotoxic challenge showed a significant impairment in the Morris water maze test when compared with animals exposed to the excitotoxic challenge but not the gestational stress. These findings suggest that stress during gestation, which may mimic low-level stress in human pregnancy, could be a novel risk factor for cerebral palsy.

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“…Animal models have been developed to unravel the mechanisms underlying these brain lesions. Factors that seem involved in the pathophysiology of CP in these models include hypoxia and ischemia, infection and inflammation, excitotoxicity, accumulation of reactive oxygen species, and deficiencies in growth factors (3,4). These factors seem to act in combination to cause damage to the developing white matter.…”

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confidence: 99%

Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

Fontaine

Olivier

Massonneau

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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White-matter damage is a leading cause of neurological handicap. Although hypoxia-ischemia and excitotoxicity are major pathogenic factors, a role for genetic influences was suggested recently. Thus, protracted gestational hypoxia was associated with whitematter damage (WMD) in rat pups but not in mouse pups. Indeed, microglial activation and vessel-wall density on postnatal days (P)1 and P10 were found increased in both mouse and rat pups, but cell death, astrogliosis, and myelination were only significantly altered in hypoxic rat pups. We investigated whether this species-related difference was ascribable to effects of antenatal hypoxia on the expression of glutamate receptor subunits by using immunocytochemistry, PCR, and excitotoxic double hit insult. Quantitative PCR in hypoxic mouse pups on P1 showed 2-to 4-fold down-regulation of the AMPA-receptor subunits -1, 2, and -4; of the kainate-receptor subunit GluR7; and of the metabotropic receptor subunits mGluR1, -2, -3, -5, and -7. None of the glutamate-receptor subunits was down-regulated in the hypoxic rat pups. NR2B was the only NMDA-receptor subunit that was down-regulated in hypoxic mice but not in hypoxic rat on P1. Ifenprodil administration to induce functional inhibition of NMDA containing NR2B-subunit receptors prevented hypoxia-induced myelination delay in rat pups. Intracerebral injection of a glutamate agonist produced a larger decrease in ibotenate-induced excitotoxic lesions in hypoxic mouse pups than in normoxic mouse pups. Gestational hypoxia may regulate the expression of specific glutamate-receptor subunits in fetal mice but not in fetal rats. Therefore, genetic factors may influence the susceptibility of rodents to WMD. brain damage ͉ NMDA receptors ͉ genetic factors ͉ development ͉ prematurity P eriventricular (P) WMD and subsequent cortical damage are the leading causes of cerebral palsy (CP) limited to preterm birth (1, 2). Animal models have been developed to unravel the mechanisms underlying these brain lesions. Factors that seem involved in the pathophysiology of CP in these models include hypoxia and ischemia, infection and inflammation, excitotoxicity, accumulation of reactive oxygen species, and deficiencies in growth factors (3, 4). These factors seem to act in combination to cause damage to the developing white matter.Glutamate accumulation may be a mechanism common to many risk factors for CP. Glutamate, the major excitatory neurotransmitter, acts by means of several groups of receptors, namely, NMDA, AMPA, kainate, and metabotropic receptors (mGluRs). Excessive activation of glutamate receptors may cause cell vulnerability, in part as a result of intracellular calcium influx (5, 6). Intracerebral injection of glutamate agonists into the neocortex and white matter of newborn rodents produces histological lesions that mimic the brain damage observed in preterm neonates (7-10).Several studies suggest that genetic factors may influence the susceptibility of very preterm infants to PWMD. The occurrence of CP may depend, at least in ...

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Pathophysiology of neonatal brain lesions: Lessons from animal models of excitotoxicity

Abstract: Available data point to a key role for brain macrophages and oligodendrocytes in neonatal rodent excitotoxic brain lesions and underline the impact of cytokines on these lesions.

Cited by 49 publications

References 35 publications

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

Melatonin Reduces Inflammation and Cell Death in White Matter in the Mid-Gestation Fetal Sheep Following Umbilical Cord Occlusion

Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

Vulnerability of white matter towards antenatal hypoxia is linked to a species-dependent regulation of glutamate receptor subunits

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