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BACKGROUND Hypoxic preconditioning (HPc) protects the neonatal brain in the setting of hypoxia-ischemia (HI). The mechanisms of protection may depend on activation of hypoxia inducible factor (HIF-1α). The present study sought to clarify the role of HIF-1α after HPc and HI. METHODS To induce HPc, HIF-1α knockout and wildtype mice were exposed to hypoxia at postnatal day 6. At day 7, the mice underwent HI. Brain injury was determined by histology. HIF-1α, downstream targets, and markers of cell death were measured by Western blot. RESULTS HPc protected the wildtype brain compared to wildtype without HPc, but did not protect the HIF-1α knockout brain. In wildtype, HIF-1α increased after hypoxia and after HI, but not with HPc. The HIF-1α knockout showed no change in HIF-1α after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1α knockout, but after HPc/HI, it was higher in wildtype. LAMP2 was higher in wildtype early after HI, but not later. After HPc/HI, LAMP2 was higher in HIF-1α knockout. CONCLUSION These results indicate that HIF-1α is necessary for HPc protection in the neonatal brain, and may affect cell death after HI. Different death and repair mechanisms depend on the timing of HPc.

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.

Seizures after neonatal hypoxia are difficult to treat. A recent antiepileptic safety and dose-finding study examined phenobarbital plus bumetanide, but was stopped owing to apparent futility and increased risk of hearing loss. However, this decision could have been overcautious: 0.2 mg/kg bumetanide reduced seizure burden, and might not have increased hearing loss.

Materials and methods Seven days old male Swiss mice were distributed on three groups: hypoxia (H), maternal separation (MS) and no handling (NH). H group underwent to 10% oxygen during 6 hours/day for 6 days and MS group was maintained in normoxia, but separated from their dams such as H group. When mice completed 3 months old, they were tested on locomotor activity boxes or in plus-maze. The parameters measured were erythrocyte catalase, superoxide dismutase and glutathione peroxidase (GPx) and cerebral catalase. Data were analyzed by one-way ANOVA test and Bonferroni post-hoc test, when appropriated.

112 G-Csf Prevents Long-Term Behavioral Deficits and Brain Injury Following Neonatal Hypoxia-Ischemia in Rats

Mild/Moderate Neonatal Hypoxia(MMNH) with Normal Blood Glucose Levels(BGL) Influence in Rats Maze Performance(MP). 49

Noradrenergic (NA) neurons in the brainstem are assumed to be involved in arousal mechanisms (locus coeruleus or A6) and cardio-respiratory control(nucl. tr. solitarius or A2). We have earlier reported an acute depression of NA turnover in newborn rats exposed to hypoxia (Acta Physiol.Scand.1992.144:433) The aim was now to investigate the acute effect of perinatal asphyxia and the long-term effects of chronic hypoxia on NA-turnover in the rat brain.

DEXTROMETHORPHAN (DM) AMELIORATES EFFECTS OF NEONATAL HYPOXIA ON BRAIN MORPHOLOGY AND SEIZURE THRESHOLD IN RATS. • 2239

Fetal and/or neonatal malnutrition has been reported to cause lifelong changes of the control of blood pressure and glucose control etc. according to Barker et al (Lancet 341:938-941.1993). The aim of the present study was to investigate whether chronic neonatal hypoxia could cause longterm changes of catecholamine (CA) turnover in the sympatho-adrenal system and the carotid bodies One day old male pups were exposed with their dams to mild hypoxia (10% O2) for 6 days and thereafter grew up under normoxia until sacrifice. Normoxic control and neonatal hypoxic rats were examined at 3 or 8 weeks with regard to CA turnover. The levels and turnover rates of dopamine (DA), norepinephrine(NE) were determined in sympathetic ganglia and their main target organs, the adrenals and the carotid bodies. After exposure to neonatal hypoxia the turnover rates of NE in the superior cervical, stellate and coeliac-mesenteric ganglia were significantly (p

AIM:We studied the effect of moderate hypoxia on nuclei/cytoplasm index at different levels of the parietal cortex of the rat at 1 month of age. MATERIAL AND METHODS: Eight brains coming from 2 litters of 1 month-old rats submitted to a neonatal hypoxia (Fi O2=10%) and standardized to 10 animals per litter were processed and stained with Nissl method. Random slide of each case was selected and studied by digitalized microscopic pictures of 70 μm width and all the cortical structures depth. Measurements of main nuclei and cytoplasm diameters of neurons in different layers were taken and results compared with 6 controls brought up in the same circumstances. Mann-Whitney test was used to comparisons. CONCLUSIONS: Nuclei/cytoplasm index of pyramidal cells was significantly greater among hypoxic than in control animals. We can conclude that slight hypoxic expositions can produce alterations in the rat neurons morphology in later stages of the development.

Sligth hypoxic-ischemic perinatal event can originated scare problems in later netirodevelopment, The aim of this job is to show the effects of two levels of hypoxia in a maze test resolution. Three groups of newborn Wistar rats were placed in an exposure chamber. They were keep in their mothers' cages till weaning (day 21). Days 25 and 26 they were submitted to maze trials. After fasting from day 28 until 30th, they were submitted again to a new maze trial. The variable validating the anirrals' behaviour was the number of squares crossed in the maze resolution (SC). Results and statistical analisys (ANOVA) are as follows: V5 group obtained a best profile in the learning capacity than V10 group. Number of errors (SC) decreased dramatically in V5 as happend wiht SH group, while V10 remained the same level of the first trial. However we are not sure if these effects can be exclusively related to the absence of presumed handicap rats who died, or to any other genetic/environmental factor.

Previous studies have shown that severe neonatal asphyxia and hypoxia lead to a redistribution of cerebral blood flow (CBF) with a preferential perfusion of the brain stem. The present study shows that this mechanism is operative also in moderately hypoxic newborn lambs (oxygen saturation 32.7-65.2) with a threshold of about 25% reduction in oxygen saturation. In hypoxia, the mean increase in total CBF, brain stem and telencephalic blood flow was 44%, 68% and 43%, respectively (five lambs). We found that naloxone reverses this redistribution, and that the effects of naloxone on telencephalic perfusion and cerebral metabolic rate of oxygen (CMRO2) were proportional. In hypoxia + naloxone (1 mg/kg), a further increase in total CBF, brain stem, and telencephalic blood flow of 30%, 7% and 31% was noted. We therefore suggest that the redistribution of CBF is an important opioid-mediated homeostatic mechanism, which diminishes the metabolic requirements of the newer part of the brain in hypoxia and allows a preferential perfusion of the vital structures of the brain stem.