IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis.

In mammals, programmed cell death (PCD) is a central event during brain development. Trophic factors have been shown to prevent PCD in postmitotic neurons. Similarly, cytokines have neurotrophic effects involving regulation of neuronal survival. Nevertheless, neuronal PCD is only partially understood and host determinants are incompletely defined. The present study provides evidence that the cytokine interleukin-9 (IL-9) and its receptor specifically control PCD of neurons in the murine newborn neocortex. IL-9 antiapoptotic action appeared to be time-restricted to early postnatal stages as both ligand and receptor transcripts were mostly expressed in neocortex between postnatal days 0 and 10. This period corresponds to the physiological peak of apoptosis for postmitotic neurons in mouse neocortex. In vivo studies showed that IL-9/IL-9 receptor pathway inhibits apoptosis in the newborn neocortex. Furthermore, in vitro studies demonstrated that IL-9 and its receptor are mainly expressed in neurons. IL-9 effects were mediated by the activation of the JAK/STAT (janus kinase/signal transducer and activator of transcription) pathway, whereas nuclear factor-kappaB (NF-kappaB) or Erk pathways were not involved in mediating IL-9-induced inhibition of cell death. Finally, IL-9 reduced the expression of the mitochondrial pro-apoptotic factor Bax whereas Bcl-2 level was not significantly affected. Together, these data suggest that IL-9/IL-9 receptor signaling pathway represents a novel endogenous antiapoptotic mechanism for cortical neurons by controlling JAK/STAT and Bax levels.

Melatonin prevents learning disorders in brain-lesioned newborn mice.

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.

[Premature rupture of membranes: pathophysiology of neurological impact]. / Rupture très prématurée des membranes: physiopathologie des conséquences neurologiques.

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.

Treatment-induced prevention of learning deficits in newborn mice with brain lesions.

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.

Pathophysiology of neonatal brain lesions: lessons from animal models of excitotoxicity.

AIM: The pathophysiology of perinatal brain lesions is probably complex and multifactorial. The development and characterization of distinct yet complementary animal models should help to unravel the cellular and molecular mechanisms underlying perinatal brain lesions. This paper reviews experimental data obtained in animal models of neonatal excitotoxic brain lesions that closely mimic some of the lesions found in human cerebral palsy. CONCLUSION: Available data point to a key role for brain macrophages and oligodendrocytes in neonatal rodent excitotoxic brain lesions and underline the impact of cytokines on these lesions.