Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain.

Gressèns, Pierre; Marret, Stéphane; Hill, Jonathan; Brenneman, Douglas E.; Gozes, Illana; Fridkin, Mati; Evrard, Philippe

doi:10.1172/jci119545

Cited by 173 publications

(134 citation statements)

References 54 publications

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“…Every third section was stained with cresyl violet. Previous studies (Gressens et al, 1997;Husson et al, 2002) have shown an excellent correlation between the maximal size of the lesion in the lateralmedial and fronto-occipital axes of the excitotoxic lesions. Based on these findings, we cut serial sections of the entire brain in the coronal plane for this study.…”

Section: Excitotoxic Lesions and Lesion Size Determinationmentioning

confidence: 74%

“…To test it, we used a well characterized mouse model of neonatal excitotoxic brain lesions (Marret et al, 1995;Gressens et al, 1997;Dommergues et al, 2000;Tahraoui et al, 2001;Husson et al, 2002), which mimic lesions observed in preterm and term human infants who will later develop CP. In this model, intracerebral administration of glutamate analogs acting on NMDA or non-NMDA receptors replicates the excess release of glutamate induced, among others, by hypoxic-ischemic insult (Volpe, 2001).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Excitotoxic Lesions and Lesion Size Determinationmentioning

confidence: 74%

Section: Introductionmentioning

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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“…Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells.…”

Section: Introductionmentioning

confidence: 99%

“…Based on epidemiological and experimental studies, the pathophysiology of PVL appears to be multifactorial. It potentially involves the combined toxicity of hypoxic-ischemic insults, excess free radicals, maternal-fetal infection with increased cytokine production, and growth factor deficiency (1,(3)(4)(5)(6)(7)(8). Excess release of glutamate and the subsequent overactivation of the excitotoxic cascade could represent a common molecular pathway for several of these risk factors (6, 9).…”

mentioning

confidence: 99%

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

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IntroductionPeriventricular leukomalacia (PVL) is a hemispheric white-matter lesion that is often cystic and occurs most frequently in infants born before 32 weeks of gestation (1). PVL is the major cause of cerebral palsy among premature infants (2). Based on epidemiological and experimental studies, the pathophysiology of PVL appears to be multifactorial. It potentially involves the combined toxicity of hypoxic-ischemic insults, excess free radicals, maternal-fetal infection with increased cytokine production, and growth factor deficiency (1,(3)(4)(5)(6)(7)(8). Excess release of glutamate and the subsequent overactivation of the excitotoxic cascade could represent a common molecular pathway for several of these risk factors (6, 9).Findings from several experimental studies support this hypothesis. Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells. Newborn mice were injected intracerebrally with sense, antisense, or missense oligonucleotides specific for the NMDA R1 receptor subunit (P. Gressens, unpublished work). The sequences of the oligonucleotides were identical to those previously used by Wahlestedt et al. in an in vitro assay (17). In newborn mice, pretreatment with antisense oligonucleotides was neuroprotective while control sense oligonucleotides had no effect on the ibotenate-induced lesion. Unexpectedly, missense oligonucleotides, which were used as another control, induced a threefold reduction in the severity of the excitotoxic whitematter lesions. A search of databases with Basic Local Alignment Search Tool (BLAST) revealed that 12 successive nucleotides of the so-called "NMDA R1 missense oligonucleotide" were actually complementary to a triplicated motif of the murine nociceptin (NC) mRNA, suggesting that the blockade of NC production is neuroprotective in the ibotenate model. Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective µ receptor agonist), nor ibot...

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“…PACAP on the other hand represses antigen presenting cell activities initiated by macrophages and dendritic cells (Kato et al, 2004). In the CNS these anti-inflammatory reactions induced by VIP and PACAP are protective in the MS environment where anti-inflammatory reactions are minimal Gressens et al, 1997). Additionally damaged neurons of the CNS may release VIP and PACAP perhaps as a restorative mechanism, in an attempt to rescue homeostasis in the CNS and this has been confirmed by down regulation of molecules such as, TNF-a, IL-6, IL-1 and overactive microglia .…”

Section: Multiple Sclerosismentioning

confidence: 99%