Role Of Toll-Like Receptor 4 On Hyperoxia-Induced Brain Injury In The Newborn Mouse

Objective: The survival rate of premature infants, especially the very low birth weight children, is significantly improved as the development of tocology and newborn infant emergency medicine, however, the incidence rate of functional developmental defects in corresponding nerves increases significantly. Causes of brain damage in preterm children are very complex, maybe concerning with ischemia and hypoxia, inflammation, cerebral hemorrhage, cerebral infarction and other factors. In recent years, oxygen therapy maybe regarded as iatrogenic injury factor to which people pay more attention increasingly. The current study confirmed that non-physiological hyperxia exposure of immature brain whose generate mechanism is not fully understood may be one of the reasons for long-term cognitive functional defects and movement disorders. TLR4 is the important pattern recognition receptors in innate immunity, and is also the first line of defense that host resists the invading of pathogenic microorganisms outside. Recent studies have found that TLR4 signaling pathway plays a critical role in the damage of central nervous system, and participates in the development of cerebral infarction, hypoxic ischemic encephalopathy, cerebral contusion and other non-infectious brain injury. This study is to investigate the effect that TLR4 signaling pathway has on the hyperxia brain injury in newborn mice.Methods Totally 48 postnatal day 1 mice, including 24 TLR4 wild-type(TLR4W) and 24 TLR4 mutant mice(TLR4M) were used in the experiment, which were randomly divided into hyperoxia group exposed in 100% oxygen 2 day(TLR4WO2,TLR4MO2) and control group exposed in the air(TLR4WA,TLR4MA)(n=12) respectively. At postnatal day 4, 6 of each group randomly were selected, of which brain tissues were removed and fixed for crysyl voilet staining in order to estimate neuronal density in prefrontal cortex, parietal cortex, and hippocampus(CA1 and dentate gyrus), and in situ death detection using terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) reaction. The remaining 6 mice in each group were bred until postnatal day 28 especially for Morris water maze.Results Neuronal density of the investigated brain areas, including prefrontal cortex, parietal cortex, and hippocampus dentate gyrus, were significantly decreased in TLR4WO2 group compared to TLR4WA group(P<0.05), with increased cell apoptosis(P<0.05). The escape latency of TLR4WO2 group after trains was shorter than control group(P<0.05), and the time in target quadrant and the number of times through virtual platform were also increased in TLR4WO2 group when compared to the contro(lP<0.05). Nevertheless,different results between TLR4MO2 group and TLR4MA group had not been observed.Conclusion Our results suggest that TLR4 singling may be involved in hyperoxia-induced immature brain injury. Loss of normal function of TLR4 may be responsible for decreased neuronal loss and apoptosis with improved behavior performance after oxygen exposure of newborn mice.