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Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. These injuries are chiefly ascribable to marked susceptibility of the immature brain to glutamate-induced excitotoxicity. No treatments are available. One well-characterized model of perinatal brain injuries consists in injecting the glutamate analog ibotenate into the brain of 5-day-old mice. The resulting excitotoxic lesions resemble the hypoxic-ischemic gray-matter lesions seen in full-term and near-term newborns, as well as the white-matter lesions of preterm newborns. We previously reported that these lesions disrupted odor preference conditioning in newborn mice. The aim of this study was to assess the effectiveness of the neuroprotector melatonin in preventing learning disabilities in newborn mice with ibotenate-induced brain injury. In postnatal day (P) 6-P7 pups, we tested psychomotor reflexes, spontaneous preference for maternal odors as an index of memory, ultrasonic vocalization responses to stroking as an index of sensitivity to tactile stimuli, and conditioned preference for an odor previously paired with stroking as an index of learning abilities. Without melatonin, conditioning was abolished, whereas spontaneous odor preference, psychomotor reflexes, and sensitivity to tactile stimuli were normal. Thus, abolition of conditioning was not associated with sensorimotor impairments. Histological analysis confirmed the efficacy of melatonin in reducing white-matter lesions induced by ibotenate. Furthermore, treatment with melatonin protected the ability to develop conditioning. Thus, melatonin, which easily crosses the blood-brain barrier and has been proven safe in children, may be effective in preventing learning disabilities caused by perinatal brain injuries in human preterm infants.

The premature rupture of membranes (PROM) is responsible for 30 % of the premature births because of a high risk of associated chorioamnionitis. PROM and the perinatal infection are recognized as 2 of the main risk factors of periventricular leukomalacia and white matter disease in very preterm neonates. Inflammation associated with PROM is likely to induce neuronal or glial cell death at a developmental stage of great vulnerability for the developing brain. Several mechanisms (release of cytokines, accumulation of free radicals, excitotoxicity, apoptosis...) account for this deleterious effect. The decision to actively extract a fetus subjected to a fetal inflammatory response syndrome should take account of the risks of a proved intrauterine infection for both the mother and the fetus and the risks for the neonate related to a very preterm birth per se. A reasonable attitude seems not to maintain a fetus in an undoubtful septic context in utero if a preterm birth in the very short term appears unevitable. Practically, no consensus gives a recommendation between aggressive or conservative management in case of PROM within 30 and 34 weeks'gestation. Expectant management seems to be indicated before 28 weeks'gestation and intentional delivery could be recommended beyond 34 weeks'gestation due to increased maternal risks compared to relatively low incidence of the complications of prematurity at this term.

Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. The molecular and cellular mechanisms of these injuries and potential pharmacological treatments are emerging, chiefly from studies in newborn rodents. In newborn mice, experimentally induced lesions can be dramatically reduced by appropriate neuroprotective treatments. However, the early effectiveness of these treatments in preserving cognition remained unknown. Here, we addressed this issue by using intracerebral ibotenate to induce excitotoxic brain lesions in 5-day-old mice (postnatal day 5). On postnatal days 6-7, we tested spontaneous preference for maternal odors, as an index of odor memory, and conditioned preference for an artificial odor previously paired with stroking, as an index of associative learning. Brain-lesioned newborn mice showed normal general status and preference for maternal odors. In contrast, odor conditioning was severely impaired. A previous study showed that fructose 1,6-biphosphate acted as a neuroprotective agent which significantly reduced neocortical lesion size. In the present study, treating the newborn mice with fructose 1,6-biphosphate 15 min before the ibotenate injection reduced neocortical lesion size and restored conditioning. This demonstrates, for the first time, that neuroprotective treatment can protect some features of early cognition.