Developmental neuroscience
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Striatal neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI, striatal neurons develop oxidative stress and organelle disruption by 3-6 h of recovery and ischemic cytopathology over 6-24 h of recovery. We tested the hypothesis that early treatment with the antioxidants EUK-134 (a manganese-salen derivative that acts as a scavenger of superoxide, hydrogen peroxide, nitric oxide or NO and peroxynitrite) or edaravone (MCI-186, a scavenger of hydroxyl radical and NO) protects striatal neurons from HI. ⋯ Treatment with EUK-134 reduced the HI-induced formation of protein carbonyl groups and tyrosine nitration at 3 h of recovery. We conclude that systemic administration of antioxidant agents by 30 min after resuscitation from HI can reduce oxidative stress and salvage neurons in the highly vulnerable striatum in a large-animal model of neonatal HI. Therefore, oxidative stress is an important mechanism for this injury, and antioxidant therapy is a rational, mechanism-based approach to neuroprotection in the newborn brain.
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Intrauterine inflammation is known to be a risk factor for the development of periventricular leukomalacia (PVL) and cerebral palsy. In recent years, activated microglial cells have been implicated in the pathogenesis of PVL and in the development of white matter injury. Clinical studies have shown the increased presence of activated microglial cells diffusely throughout the white matter in brains of patients with PVL. ⋯ This was also associated with increased numbers of activated microglia (mean ratio ± SD of activated to total microglia: 0.96 ± 0.16 in the endotoxin group vs. 0.13 ± 0.08 in controls; p < 0.001) in the internal capsule and corona radiata. Our findings indicate that the magnitude of [(11)C]PK11195 binding measured in vivo by PET imaging matches the severity of motor deficits in the neonatal rabbit. Molecular imaging of ongoing neuroinflammation in the neonatal period may be helpful as a screening biomarker for detecting patients at risk of developing cerebral palsy due to a perinatal insult.
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The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come 'indirectly', through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. ⋯ These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of 'indirect' prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.
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The immature brain is susceptible to inflammatory injury induced by hypoxia-ischemia (HI) or infection, which causes serious neurodevelopmental disabilities in the survivors of preterm births. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (death receptor DR4/5 and decoy receptor DcR1/2) were reported to mediate various neuroinflammatory responses. However, little information is available regarding the role of TRAIL and its receptors in the immature brain after HI. ⋯ Furthermore, the HI group displayed impaired neurobehavioral development compared with the control group (p < 0.05). Altogether our results show that the TNF-α superfamily ligand TRAIL is induced on CD68+ microglia/macrophages after perinatal HI and that one of its receptors, DR5, is induced on neocortical neurons and glial cells. That many DR5+ cells were also caspase-3+ strongly supports the conclusion that these signaling molecules are involved in the delayed loss of neurons in the neocortex and in the neurobehavioral deficits that are often seen after perinatal HI.
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Hypothermia is the most effective neuroprotective therapy against ischemic injury in the developing brain. However, the mechanism of hypothermic neuroprotection is not well understood. We sought to investigate whether hypothermia mediates neuroprotection by modulating ischemia-induced apoptosis. ⋯ Hypothermic modulation of caspase-dependent apoptosis may be mediated by upregulating XIAP. However, the effect of hypothermia on caspase-independent apoptosis may be mediated by XIAP-independent mechanisms. Importantly, these effects are mediated in both the core and the penumbral regions of ischemic lesion.