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Few data are available on the involvement of brain microvascular endothelial cells (BMECs) in excitotoxic neonatal brain lesions. Therefore, we developed an original approach for investigating mouse-derived BMECs in vitro. We hypothesized that newborn and adult BMEC cultures would show age-related differences in phenotype and sensitivity to glutamate. Expression of the monocarboxylate transporter, MCT1, was higher in neonatal than in adult BMECs, whereas expression of the glucose transporter, GLUT1, was higher in adult than in neonatal BMECs that overexpressed the N-methyl-D-aspartate receptor NR1 subunit (NMDAR1) compared with adult BMECs. The ability of neonatal and adult BMECs to be activated by glutamate was confirmed through intracellular calcium ([Ca2+]i) recording. The glutamate-induced [Ca2+]i increase was blocked by the selective NMDAR antagonist, MK-801. Significant glutamate-evoked concentration-dependent release of tissue-type plasminogen activator (t-PA) and matrix metalloproteinases (MMPs) activities was found in supernatants of neonatal, but not in adult BMECs. The glutamate-mediated release of t-PA, MMP-2, and MMP-9 proteolytic activities in neonatal BMECs was blocked by MK-801. Conceivably, this protease release from neonatal BMECs may participate in neonatal brain lesions.

Resume La protection du cerveau en developpement de l’enfant ne premature reste un challenge pour les neonatalogistes. Malgre une production scientifique importante mettant en evidence des effets protecteurs de nombreuses molecules dans differents modeles animaux in vitro et in vivo de lesions cerebrales acquises, les applications en medecine perinatale restent rares du fait notamment des difficultes a connaitre le moment de l’initiation de la cascade deletere aboutissant aux lesions cerebrales et des effets toxiques de nombreuses molecules candidates a un effet protecteur. L’objet de cette revue est de faire le point sur le potentiel neuroprotecteur de plusieurs molecules utilisees couramment en medecine perinatale. Le sulfate de magnesium donne aux femmes enceintes comme tocolytique ou comme traitement de la pre-eclampsie n’a pas montre d’effets deleteres lorsqu’il est donne a faible dose a visee neuroprotectrice a une femme en menace d’accouchement imminent. Dans l’essai randomise francais, un benefice non significatif sur le taux de paralysie cerebrale et de dysfonctionnement moteur a deux ans a ete observe tandis que le benefice sur le critere combinant deces et/ou anomalie motrice a 2 ans etait significatif. Ces donnees ne permettent pas de recommander le traitement en routine mais justifient de poursuivre l’analyse des effets a long terme et de considerer cette molecule comme traitement preventif ou en association dans d’autres essais therapeutiques. Pour ce qui concerne la corticotherapie antenatale, un benefice sur la survenue des leucomalacies periventriculaires et des atteintes de la substance blanche est note dans le groupe des 28-32 semaines en presence de corticoides mais celui-ci n’est pas observe sur le devenir a long terme ni sur les troubles du comportement ni dans le groupe des 24-27 semaines. La cafeine, dont le benefice est demontre depuis plusieurs annees dans le traitement des apnees, a un potentiel neuroprotecteur puisque elle diminue significativement les taux de paralysie cerebrale et/ou de difficultes intellectuelles a 2 ans lorsqu’elle est donnee vers la fin de la premiere semaine pour traiter les apnees du premature. D’autres molecules telles que l’indometacine, le phenobarbital, l’oxyde nitrique inhale, la vitamine E ou l’erythropoietine sont par contre sans effet protecteur cerebral voire pourraient aggraver la morbidite neurologique pour certaines telles que l’indometacine administree avant la naissance. Enfin compte tenu de leurs proprietes, l’aspirine ou les anesthesiques voire les differents tocolytiques devraient etre etudies rapidement dans des etudes d’observation.

With improving neonatal survival for very premature babies, the challenge for neonatalogists is to ameliorate outcome of surviving babies. Several pharmacological molecules have been shown to have protective effects in different types of in vitro or in vivo animal models of acquired cerebral brain damages. However translational research and conduction of therapeutic trials in human remain difficult due to failure to recognize start of deleterious cascade leading to cerebral damage and additional toxic effect of potential protective molecules. This review concentrates on best evidence emerging in recent years on prevention on brain damage by early drug administration. It has been shown in two randomised trials that prenatal low-dose of magnesium sulphate does not increase paediatric mortality in very-preterm infants and has non significant neuroprotective effects on occurrence of motor dysfunction (with a 0.62 odds ratio in the French trial Premag and 0.71 relative risk in the Australian trial ACTOMgSO4), justifying that magnesium sulphate should be discussed as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials. Antenatal corticosteroid therapy increases the survival of very-preterm infants, including the most immature. Moreover in an observational recent study of the Epipage cohort, it has been observed a significant decrease in white matter injury in the 28-32 weeks' gestation group but no effect on long term outcome and behaviour. Conversely in the most immature of the 24-27 weeks' gestation group, no effect has been detected either in white matter injury incidence or in long term outcome rates. Caffeine has a protective effect since a decrease in cerebral palsy has been noted in the caffeine group in a randomised trial studying caffeine versus placebo. For what concern other widely used potential protective molecules during the perinatal period, there is no evidence of cerebral protection with indometacine, nitric oxide, eythropoietin, phenobarbital, and etamsylate. Due to their specific properties, a careful evaluation of aspirin, anaesthetic drugs and tocolytics should be done in the next months.