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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.

BackgroundHypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI.MethodsRats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole-body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham-treated animals not subjected to HI were also studied.ResultsDifferences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects.ConclusionNo significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy.

The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide, a clinically available diuretic, inhibits this chloride transporter, and augments the antiepileptic effects of phenobarbital in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O2 exposure in 7-day-old(P7) rats, phenobarbital(PB) increases the neuroprotective efficacy of hypothermia. We evaluated whether bumetanide influenced the neuroprotective efficacy of combination treatment with PB and hypothermia(HT). P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg). 10 min later, half received bumetanide (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30°C, 3h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1 to 4 weeks later. Forepaw functional measures were close to normal in the PB-HT+BUM group, while deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21±16 versus 38±20 in controls). These results provide evidence that NKCC1 inhibition amplifies phenobarbital bioactivity in the immature brain, and suggest that co-administration of phenobarbital and bumetanide may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic hypothermia in asphyxiated neonates.

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.