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Biomedical subjects

P Evrard

Publications and source records attributed to P Evrard.

At least 19 recordsLinked to original sources
PubMed1999

[Prenatal inhibition of intestinal vasoactive peptide and cerebral excitatory lesions in the newborn mouse].

The glutamatergic agent ibotenate induces cortical plate and white matter lesions in the newborn mouse, mimicking brain lesions of the human neonate. In this model, co-treatment with ibotenate and a vasoactive intestinal peptide antagonist (VA) aggravates the excitotoxic lesions, suggesting a protective role of endogenous VIP. On the other hand, prenatal injection of VA is followed by a dramatic depletion of astrocytes in the neocortex. Since astrocytes produce numerous neuronotrophic agents, we studied the consequences of a decreased astrocytic density by prenatal VIP blockade on the excitotoxic brain lesions in newborn mice. Pregnant females were pre-treated with VA during the last 2 days of gestation and ibotenate was intracerebrally injected on postnatal day (P) 2 or P5. When compared to controls, pups pre-treated with VA and injected with ibotenate at P2 displayed a significant reduction of the white matter lesion size while cortical plate lesion was not affected. This protective effect disappeared when ibotenate was injected at P5. White matter protection by VA pre-treatment did not seem to be linked to the decreased astrocytic density since, i) this astrocytic paucity concerns only superficial cortical layers and does not affect white matter, ii) protective effects are only observed at P2 while astrocytic density reduction is observed at P2 and P5. This white matter protection could be secondary to an up-regulation of VIP receptors: an increased density of VIP receptors, which was described in other developmental models following VA treatment, could increase the efficacy of the endogenous VIP after an excitotoxic insult.

Animals↗
PubMed1999

Glycine antagonist and NO synthase inhibitor protect the developing mouse brain against neonatal excitotoxic lesions.

The prevention of cerebral palsy and neuroprotection of the immature brain continue to be health care priorities. The pathophysiology of perinatal brain lesions associated with cerebral palsy seems to be multifactorial and includes pre- and perinatal factors such as preconceptional events, hormone and growth factors deficiencies, maternal infections with production of cytokines, and hypoxic/ischemic perfusion failures. Excitotoxic cascade could represent a common pathway that leads to neural cell death and subsequent brain damage. Brain injuries induced by ibotenate, a glutamatergic analog, which are essentially mediated through the N-methyl-D-aspartate receptor, mimic some aspects of the white matter cysts and transcortical necrosis observed in human perinatal brain damage. The purpose of the present study was to assess the protective role of several pharmacological agents, administered in conjunction with ibotenate, against induced excitotoxic lesions. We injected ibotenate in the developing mouse brain 5 d postnatally, after the full settlement of neuronal layers. Co-treatment with kynurenic acid, an antagonist of the facilitating glycine site of the N-methyl-D-aspartate receptor, or with N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, induced a dose-dependent neuroprotective effect. Conversely, zinc gluconate, a blocking agent of the channel linked to the N-methyl-D-aspartate receptor, and a free radical scavenger (U74389F), were unable to protect the developing brain against excitotoxic attack. These data help to clarify some molecular mechanisms involved in excitotoxic lesions of the developing mouse brain and permit us to envision new strategies in the prevention of cerebral palsy.

Animals↗
PubMed1999

Successful double lung transplantation with a graft obtained from a methanol-poisoned donor.

A 25-year-old woman developed "brain death" 48 h after acute methanol poisoning. After the elimination of methanol and the correction of metabolic disorders, organ donation was discussed. The lungs were transplanted into a 46-year-old woman suffering from cystic "emphysematous-like" lesions as a complication of lymphangioleiomyomatosis. The procedure was not complicated, and we have an uneventful follow-up of > 12 months. In addition to the lungs, the kidneys and the liver were also removed and transplanted with success.

Acute Disease↗
PubMed1999

Neuroprotection of the developing brain by systemic administration of vasoactive intestinal peptide derivatives.

Periventricular leukomalacia (PVL), a necrotic and often cystic lesion of the cerebral white matter occurring in very premature babies, is the leading cause of cerebral palsy in this population. Increased glutamate release and the excitotoxic cascade thus triggered may be critical factors in the development of PVL. The glutamatergic analog ibotenate injected intracerebrally into newborn mice produces white matter cysts that mimic human PVL. Concomitant injection of vasoactive intestinal peptide (VIP), a trophic factor, protects the white matter against excitotoxic lesions. The goal of the present study was to assess the protective properties of systemically injected VIP analogs against ibotenate-induced excitotoxic white matter lesions in newborn mice. VIP analogs were selected on the basis of their low susceptibility to endopeptidases and their potential ability to cross biological membranes. RO-25-1553, a long-lasting cyclic VIP analog, and stearyl-norleucine-VIP, a fatty derivative of VIP, reduced ibotenate-induced white matter cysts by up to 87% and 84%, respectively, when injected i.p. immediately after ibotenate. By comparison, i.p. coadministration of VIP and ibotenate was not protective against the excitotoxic insult. Furthermore, RO-25-1553 and stearyl-norleucine-VIP still induced significant neuroprotection of the developing white matter when injected systemically 8 and 12 h, respectively, after ibotenate, establishing these peptides as therapeutic agents in this murine model. VIP analogs may have therapeutic potential in human premature babies at high risk for PVL.

Amino Acid Sequence↗
PubMed1998

In contrast to cocaine, prenatal exposure to methadone does not produce detectable alterations in the developing mouse brain.

Whereas prenatal cocaine exposure dramatically alters brain development, the safety of methadone in detoxification programs for heroin-addicted pregnant women is uncertain. This paper compares the effects of exposure to methadone or to cocaine in utero on a model system, the developing mouse brain. Methadone (40 mg/kg/day, i.e., 40-fold detoxification dosage) or cocaine (30 mg/kg/day, as in severe addiction) was injected into mice from day 8 to day 18 of gestation. Pre- and postnatal brain development was analyzed at the anatomical and microscopical levels, including by immunostaining of post-mitotic cells, neurites, and astrocytes. Prenatal mice exposure to cocaine caused neuronal misaddressing among neocortical layers, abnormal gliogenesis, and defective neuritic outgrowth and bundling. Methadone produced small-for-date offspring with normal brain development. In conclusion, supratherapeutic methadone doses induce intrauterine growth retardation in mice, but spare brain cytoarchitecture. In contrast, cocaine produces less growth retardation, but severely disturbs neocortical layering.

Aging↗
PubMed1998

Long-term evolution of excitotoxic cortical dysgenesis induced in the developing rat brain.

Cortical dysplasias are frequently caused by excitotoxic brain damage due to hypoxia or ischemia during development. Ibotenate, a glutamatergic agonist, was injected in the neopallium of rat pups at day of birth. The resulting cytoarchitectonic pattern includes neuronal depopulation in deep cortical layers, sulcus formation, and molecular ectopias, mimicking human polymicrogyria and disorders of neuronal migration. These cortical dysplasias persist until adulthood, providing a rat model to investigate the long-term functional consequences of cortical malformations.

Abnormalities, Drug-Induced↗
PubMed1998

Selective direct toxicity of cocaine on fetal mouse neurons. Teratogenic implications of neurite and apoptotic neuronal loss.

This chapter reviews epidemiologic clinical surveys and experimental animal studies, indicating that cocaine may induce severe teratogenic effects on the developing brain. Evidence for direct toxic effects is next presented. Using cocultures of embryonic brain cells, we demonstrate that cocaine selectively affects neuronal cells, first causing a dramatic reduction in the number and length of neurites, then extensive neuronal death by apoptosis. By contrast, cocaine affected neither the abundance of astroglial cells nor their glial fibrillary acidic protein content. These effects are not due to cocaine metabolites. The contributions of indirect and direct effects that could account for cocaine neuroteratogenicity are finally discussed.

Animals↗
PubMed1998

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties.

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.

Acoustic Stimulation↗
PubMed1998

[Prenatal diagnosis and outcome of patients with spina bifida].

The frequency of new cases of myelomeningocele has largely decreased in the last 10 years in several countries of western Europe; the emergence of widespread prenatal diagnosis is probably one of the main reasons. However, the outcome of spina bifida which eludes the prenatal diagnosis, or in cases where termination was refused by parents, remains badly known. To our knowledge, there is no recent data on the outcome of children with spina bifida. Moreover, available data, depending on their European or American origin, indicate different functional outcomes. This led us to re-evaluate the mechanisms involved in the prenatal diagnosis of spina bifida and the outcome of our patients with spina bifida. The aim of this paper is to give a short description of the "rules and principles" of prenatal diagnosis as it is applied in our centres, as well as a brief overview of the outcome of 137 cases of spina bifida. In the retrospective study, three major aspects were evaluated: 1) frequency and types of surgeries and their benefits; 2) socio-psychological adaptation of the patients; 3) educational level and learning disabilities.

Adaptation, Psychological↗
PubMed1998

[Periventricular leukomalacia. I. Histological and pathophysiological aspects].

The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. PVLs are found post-mortem in one third of brains from autopsies of premature infants; PVLs are diagnosed in 4 to 10% of infants born before 33 weeks of gestation and remaining alive more than 3 days after birth. PVL is very rare in at term infants. The proportion of PVLs from prenatal origin is estimated between one third and one half of cases. Recent progresses in neuroepidemiology, developmental neurobiology and imaging methods permit to revisit the pathophysiology of PVLs on a multifactorial basis. The final result of these multiple factors seem to be calcium influx due to glutamatergic overactivation triggered by cytokines, infection and inflammation, and deficit in neurotrophic factors. Periventricular topography can be explained by properties of intracerebral vascular wall at this stage of angiogenesis and by perfusion failure/hypoxia.

Humans↗
PubMed1998

[Periventricular leukomalacia and brain protection. II. Diagnosis, sequelae and neuroprotection].

The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. Carrying motor and neuropsychological consequences, PVLs could be the most severe danger for very premature brains. Positive rolandic sharp waves recorded on EEG and precocious abnormally echogenous periventricular images on ultrasound suggest prospective periventricular cysts. Cystic periventricular cavitations certify the diagnosis of PVL. More subtle lesions of PVL do not reach the cystic grade and their diagnosis is confirmed by MRI. Treatment of infections is already available and potentially a tool for prevention. When the overwhelming glutamatergic signal has been triggered, neuroprotective agents turning off the excitotoxic cascade, including calcium blockers, growth factors and others, are promising therapeutic tools.

Humans↗
PubMed1998

Vasoactive intestinal peptide shortens both G1 and S phases of neural cell cycle in whole postimplantation cultured mouse embryos.

Vasoactive intestinal peptide, a trophic and mitogenic factor, stimulates growth in whole cultured mouse embryos. Inhibition of this growth function between embryonic days 9 and 11 induces growth retardation accompanied by severe microcephaly. In the present study, to determine the effects of this peptide on the different phases of the cell cycle of neural cells, embryonic day 9.5 cultured mouse embryos were cumulatively labelled with bromodeoxyuridine. Vasoactive intestinal peptide (10(-7)M) shortened S phase and G1 phase of neuroepithelial cells by 50% (4.8-2.4 h) and 58% (1.9-0.8 h), respectively, compared with controls. G2 and M phases were not modified by vasoactive intestinal peptide treatment. Total cell cycle length was consequently reduced by 43% (8.2-4.7 h) in vasoactive intestinal peptide treated embryos, compared with controls. In contrast, vasoactive intestinal peptide did not modify the rate of neuroepithelial cell death as assessed by the proportion of nuclei containing fragmented DNA. These data suggest that vasoactive intestinal peptide stimulates growth in premigratory stages of nervous system development by shortening S and G1 phases of the cell cycle and that S phase duration can be regulated by a physiological peptide.

Animals↗
PubMed1998

Involvement of pituitary adenylate cyclase-activating polypeptide II vasoactive intestinal peptide 2 receptor in mouse neocortical astrocytogenesis.

At the end of neuronal migration, the neopallial germinative zone produces glial cells destined to colonize the upper layers of neocortex. High densities of binding sites for vasoactive intestinal peptide (VIP) have been found in the rodent germinative zone just after completion of neuronal migration, suggesting a possible role of VIP in neocortical astrocytogenesis. In the present study, administration of a VIP antagonist at embryonic days 17 and 18 to pregnant mice was followed by a dramatic depletion of astrocytes in the upper cortical layer of the offspring. The depletion of astrocytes was dose-dependent, with a 42% reduction in the density of astrocytes observed with 50 microg of antagonist. The antagonist effect was reversed by cotreatment with VIP or pituitary adenylate cyclase-activating polypeptide (PACAP), suggesting the involvement of a receptor common to these two neuropeptides. VIP antagonist-induced inhibition of astrocytogenesis was also blocked by Ro 25-1553, a long-acting cyclic VIP analogue selective for the PACAP II VIP2 receptor subclass. Our results demonstrate that VIP and/or PACAP play a crucial physiological role in neocortical astrocytogenesis, possibly through interaction with PACAP II VIP2 receptors.

Animals↗
PubMed1998

Regulation of neuroprotective action of vasoactive intestinal peptide in the murine developing brain by protein kinase C and mitogen-activated protein kinase cascades: in vivo and in vitro studies.

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white matter lesions mimicking periventricular leukomalacia, the most frequent brain lesion occurring in premature human babies. In this model, coinjection of vasoactive intestinal peptide prevents white matter lesions. In the present study, coadministration of ibotenate, vasoactive intestinal peptide, and selective transduction inhibitors showed that protein kinase C and mitogen-associated protein kinase pathways were critical for neuroprotection. In vivo and in vitro immunocytochemistry revealed that vasoactive intestinal peptide activated protein kinase C in astrocytes and neurons, and mitogen-associated protein kinase in neurons. In vitro neuronal transduction activation was indirect and required medium conditioned by astrocytes in which protein kinase C had been activated by vasoactive intestinal peptide. Although vasoactive intestinal peptide did not prevent the initial in vivo appearance of white matter lesion, it promoted a secondary repair of this lesion with axonal regrowth. Through protein kinase C activation, vasoactive intestinal peptide also prevented ibotenate-induced white matter astrocyte death. These data support the following hypothetical model: Vasoactive intestinal peptide activates protein kinase C in astrocytes, which promotes astrocytic survival and release of soluble factors; these released factors activate neuronal mitogen-associated protein kinase and protein kinase C, which will permit axonal regrowth.

Animals↗
PubMed1998

Microlissencephaly: a heterogeneous malformation of cortical development.

We report the neonatal courses, early postnatal development, and neuroimaging findings of 17 patients with marked microcephaly and simplified cerebral gyral patterns, a condition that we call microlissencephaly. Retrospective analyses of the clinicoradiologic features of these patients allowed segregation of the patients into 5 distinct groups with varying outcomes. The apparent discreteness of these groups suggests multiple etiologies of this malformation, although there appears to be a strong genetic component with probable autosomal recessive inheritance. Utilizing the neonatal course and neuroradiologic features of these infants allows classification of specific subsets, which may be useful to predict outcome.

Cerebral Cortex↗