Data indicate that bacterial products in combination with other antenatal or postnatal exposures increase the risk of perinatal brain injury. We have previously shown that administration of lipopolysaccharide (LPS) 4 h before hypoxia-ischemia (HI) increases brain injury in 7-d-old rats. The mechanisms behind such sensitization are unclear, but contrasts against a preconditioning effect of LPS given 1-3 d before ischemia in adult animals. To investigate how the effects of LPS depend on the time interval between administration and HI in the developing brain, we evaluated the effect of varying time interval (2-72 h) between LPS and HI, the duration of HI (20 or 50 min), and age of the rat pups (postnatal d 4 or 7). Outcome was assessed by brain injury scoring of specific regions. We found that LPS reduced brain injury (by 78%) when administered 24 h before 50 min of HI. However, when LPS was administered 6 h before either 20 or 50 min of HI, brain injury was increased by 2026% and 137%, respectively. Even LPS given 72 h before HI increased injury, both when LPS was administered at postnatal d 4 (by 446%) and 7 (by 77%). In conclusion, LPS enhanced vulnerability in the developing brain both in the acute (4 -6 h) and the chronic (72 h) phase after administration, whereas an intermediate interval between LPS and HI had the opposite effect. The long-term sensitizing effect of LPS has not been previously described. (Pediatr Res 58: 112-116, 2005) Abbreviations DAB, 3,3-diaminobenzidine HI, hypoxia-ischemia LPS, lipopolysaccharide MAP-2, microtubule-associated protein-2 MCAO, middle cerebral artery occlusion NF-B, nuclear factor-kappaB PND, postnatal day TGF-␤1, transforming growth factor-␤1 TNF-␣, tumor necrosis factor-␣ The etiology of newborn encephalopathy is complex and many causal pathways have been suggested to operate antenatally and to interact with intrapartal and postnatal factors (1,2). Antenatal infection has been identified as one cause of encephalopathy and cerebral palsy (1,3,4), acting alone or in combination with other events such as potentially asphyxiating conditions during birth (5).We previously showed that the combination of a low-dose LPS and a sub-threshold period of HI results in increased brain damage in 7-d-old rats, implicating that bacterial products sensitize the immature brain (6). We also detected an increase in CD14 mRNA in the neonatal brain, suggesting activation of the innate immune system. Recently, we explored the effect of peripheral LPS on global gene expression in the immature CNS (unpublished observations). Multiple genes were regulated in a sequential manner with specific patterns of expression at different time points after LPS, suggesting that CNS vulnerability may depend on the time interval between LPS and the subsequent insult. Indeed, previous studies in the adult setting show that a single dose of LPS before permanent MCAO reduced brain injury when LPS was injected 2-4 d before MCAO (7,8). Furthermore, it is well recognized that the neurodevelopmental stage is important ...

Free radicals seem to be involved in the development of cerebral white matter damage after asphyxia in the premature infant. The immature brain may be at increased risk of free radical mediated injury, as particularly the preterm infant has a relative deficiency in brain antioxidants systems, such as superoxide dismutase and glutathione peroxidase. In vitro studies show that immature oligodendrocytes express an intrinsic vulnerability to reactive oxygen species and free radical scavengers are able to protect immature oligodendrocytes from injury. The aim of this study was to examine the formation of ascorbyl radicals as a marker of oxidative stress in the preterm brain in association with cerebral white matter injury after intrauterine asphyxia. Fetal sheep at 0.65 gestation were chronically instrumented with vascular catheters and an occluder cuff around the umbilical cord. A microdialysis probe was placed in the periventricular white matter. Fetal asphyxia was induced by occlusion of the umbilical cord for 25 min (n ϭ 10). Microdialysis samples were collected for 72 h and analyzed for ascorbyl radicals using electron spin resonance. Five instrumented fetuses served as controls. Three days after the insult, fetal brains were examined for morphologic injury. Umbilical cord occlusion resulted in prolonged and marked increase in ascorbyl radical production in the brain in connection with white matter injury, with activation of microglia cells in periventricular white matter and axonal injury. These data suggest that reperfusion injury following asphyxia in the immature brain is associated with marked free radical production. White matter damage is a prominent form of brain injury in the premature infant and is associated with subsequent development of cerebral palsy and cognitive impairment (1,2). The lesions of the white matter can either be focal, typically localized bilaterally to the external angles of the lateral ventricles (so-called PVL), or diffuse throughout the subcortical white matter (3,4). Immaturity of the cerebral vascular architecture and poor autoregulation of cerebral blood flow are major factors related to the susceptibility of the periventricular regions to ischemia (5). The development of white matter damage in preterm infant brains and subsequent disturbance of myelination takes place in areas with abundance of oligodendrocyte progenitor cells (6).Oxidative stress resulting in the production of free radicals seems to play a key role in the pathogenesis of white matter damage. Recent studies have shown evidence of oxidative and nitrosative injury to premyelinating oligodendrocytes in autopsy brain tissue from premature infants with PVL (7) and high levels of lipid peroxidation products are found in the CSF of preterm infants with PVL (8). Immature oligodendrocytes in vitro are particularly vulnerable to reactive oxygen species, and free radical scavengers protect immature oligodendrocytes from injury (9,10).

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We have previously shown that lipopolysaccharide (LPS) sensitizes the immature rat brain to subsequent hypoxic-ischemic (HI) injury; however, the underlying mechanisms remain unclear. In this study, we examined the role of glucose in the sensitizing effects of LPS and lipoteichoic acid (LTA) in combination with HI in 7-day-old rats. LPS/HI resulted in hypoglycemia which lasted 24 h and lactate levels were increased from 6 to 10 h after LPS administration. LPS/HI induced severe brain injury, which persisted 2 weeks after LPS/HI. Administration of glucose to LPS-treated animals with HI reduced brain injury in the cerebral cortex and hippocampus, while striatal damage remained. LTA/HI did not affect blood glucose, lactate or brain injury. In conclusion, enhanced blood glucose levels during HI after LPS administration conferred protection in some brain regions but not in the striatum, suggesting that alterations in glucose can only partly explain the sensitizing effect of LPS.

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