Antenatal Bacterial Endotoxin Sensitizes the Immature Rat Brain to Postnatal Excitotoxic Injury

Rousset, Colette; Kassem, Jinane; Olivier, Paul; Chalon, Sylvie; Gressèns, Pierre; Saliba, Élie

doi:10.1097/nen.0b013e31818894a1

Cited by 45 publications

(29 citation statements)

References 40 publications

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“…Optical density was measured at ×200 magnification using a computerized image analysis system (Mercator; Explora Nova, La Rochelle, France), which reads optical density as gray levels. Nonspecific background densities were measured at each brain level in a region devoid of MBP immunostaining and were subtracted [34]. …”

Section: Methodsmentioning

confidence: 99%

Maternal Exposure to Lipopolysaccharide Leads to Transient Motor Dysfunction in Neonatal Rats

Rousset

Kassem²,

Aubert³

et al. 2013

Dev Neurosci

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Epidemiological and experimental data implicate maternal infection and inflammation in the etiology of brain white matter injury, which may lead to cerebral palsy in preterm newborns. Our aim was to investigate motor development of the offspring after maternal administration of lipopolysaccharide (LPS). Wistar rats were intraperitoneally injected with Escherichia coli LPS or saline on gestational days 19 and 20. From birth to 3 weeks, pups were tested for neurobehavioral development, neurological signs and reflexes. From 3 to 6 weeks, motor coordination was investigated. At 4 months, animals were tested for locomotion. Brain myelination was assessed by myelin basic protein immunohistochemistry. Days of appearance of several neurological reflexes were significantly delayed, and neonate LPS pups displayed retarded performance in righting, gait and negative geotaxis. At the juvenile stage, LPS animals showed important impairment in coordination. However, although the LPS group performed worse in most tests, they reached vehicle levels by 5 weeks. At 4 months, LPS animals did not show variations in locomotion performances compared to vehicle. No myelination differences have been observed in the brains at adulthood. Maternal LPS administration results in delayed motor development even though these alterations fade to reach control level by 5 weeks. Motor impairments observed at the early stage in this study could be linked to previously reported hypomyelination of the white matter induced by maternal LPS challenge in the neonates. Finally, the normal myelination shown here at adulthood may explain the functional recovery of the animals and suggest either a potential remyelination of the brain or a delayed myelination in LPS pups.

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Section: Methodsmentioning

confidence: 99%

Maternal Exposure to Lipopolysaccharide Leads to Transient Motor Dysfunction in Neonatal Rats

Rousset

Kassem²,

Aubert³

et al. 2013

Dev Neurosci

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“…Substantial numbers of preclinical studies have demonstrated the sensitizing effects of gestational or neonatal systemic inflammation, gestational chronic mild maternal stress, and gestational hypoxia on perinatal excitotoxic or hypoxic-ischaemic lesions. [16][17][18][19][20][21] Genetic factors have also been shown to influence the developing brain's response to sensitizing factors. 22,23 Robust epidemiological studies, performed in preterm and term-born neonates, support a role for inflammation as a sensitizer.…”

Section: Concept Of Inflammation-induced Sensitizationmentioning

confidence: 99%

“…20,61 Similarly, delivery of LPS to pregnant rats on the last 2 days of gestation exacerbated ibotenate-induced brain damage in postnatal day 4 pups, with the highest dose of LPS doubling the lesion size. 17 Several studies have evaluated the time window during which sensitization of the brain will persist following exposure to inflammatory factors in the perinatal period. Sensitization to hypoxic-ischaemic damage following neonatal administration of LPS appears to last at least up to 3 days in rats 62 and 14 hours in mice.…”

Section: Experimental Evidence Of Inflammation-induced Sensitization mentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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“…Immunostaining in fetuses and postnatal offspring has shown that prenatal LPS-induced inflammation in the brain of rats and mice leads to white matter damage, microglial activation, decreased hippocampal neurogenesis, dendritic alterations and decreased myelin basic protein [7,8]. Immune system disorders are often accompanied by alterations in the hypothalamic-pituitary-gonadal axis.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Maternal Inflammation Affects the Gonadotropin-Releasing Hormone Neuron Development in Fetal Mice

Sharova

Izvolskaia

Захарова

2014

Neuroimmunomodulation

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Recent studies provide evidence that prenatal immunological stress may affect the programming of reproductive health and sexual behavior in adult animals. The aim of this study was to investigate the influence of maternal inflammation, induced by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 45 µg/kg) on embryonic day 11.5 (E 11.5), on the development of the gonadotropin-releasing hormone (GnRH) system in mouse fetuses as well as on the proinflammatory cytokine level in pregnant mice and their fetuses. In the fetuses, the GnRH neuron migration from the olfactory pit to the forebrain was estimated on embryonic days 14.5 and 18.5. The levels of the proinflammatory cytokines interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α and leukemia inhibitory factor (LIF) were measured with the cytometric bead and ELISA array method in the maternal and fetal blood, amniotic fluid and fetal cerebrospinal fluid (CSF). According to our data, activation of the immune system by LPS treatment on embryonic day 11.5 leads to an increased quantity of neurons in the nasal and olfactory bulb areas and a decreased quantity in the forebrain area on embryonic day 14.5. There was a slight decrease in the total number of neurons in the forebrain area on embryonic day 18.5. The levels of proinflammatory cytokines were significantly increased within 3 h after LPS treatment in the maternal and fetal blood, amniotic fluid and fetal CSF. IL-6-receptor immunoreactivity was detected on olfactory/vomeronasal axons. Thus, prenatal immunological stress delays the GnRH neuron migration in the nasal compartment of mouse fetuses, which may be mediated by the regulation of IL-6, MCP-1 and LIF secretion in the maternal-fetal system.

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Antenatal Bacterial Endotoxin Sensitizes the Immature Rat Brain to Postnatal Excitotoxic Injury

Cited by 45 publications

References 40 publications

Maternal Exposure to Lipopolysaccharide Leads to Transient Motor Dysfunction in Neonatal Rats

Maternal Exposure to Lipopolysaccharide Leads to Transient Motor Dysfunction in Neonatal Rats

Inflammation‐induced sensitization of the brain in term infants

Lipopolysaccharide-Induced Maternal Inflammation Affects the Gonadotropin-Releasing Hormone Neuron Development in Fetal Mice

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