Oxygen restriction of neonate mouse elevates HIF-1α, IL-6,NF-κb and caspase-3 protein levels: possible relationship to neurodevelopmental disorders

Abstract

BACKGROUND: The etiological and biological mechanisms of neuropsychiatric disorders, such asschizophrenia and autism, are incompletely understood. Albeit genetic plays a major role in disease pathogenesis, about 20-30% of causation is estimated to be non-genetic or environmental. Human epidemiological studies have provided strong evidence that prenatal and/or perinatal exposure to various environmental insults, like obstetric complications, increased risk for later development of schizophrenia/autism. Animal models of obstetric complications in form of perinatal hypoxia have reliably demonstrated that a brief period of severe and acute hypoxia/ ischemia can initiate the causal sequences leading to neuronal death in otherwise healthy animals, while inappropriate activation of the apoptotic programme accounts for at least part of the cell death seen after transient hypoxia-ischemia. In attempt to delineate the possible effects of obstetric complications to the etiology of the neurodevelopmental disorders, like schizophrenia/autism, mouse model of perinatal hypoxia was used to determine whether inflammation and apoptosis are involved in the diseases pathogenesis. The expression of transcription factors, HIF-1α and NF-κB, inflammatory mediator, IL-6, and apoptotic protein, caspase-3 in the prefrontal cortex (PFC) of neonatal hypoxic mice were examined. METHODS: C57BL/6N mice were used. On postnatal day (PD) 7, mice pups were subjected to normobaric hypoxia (exposed to air mixture of 8% O2, 0.03% CO2,balance N2) versus air (exposed to air mixture of 20% O2, 0.03% CO2, balance N2) for 120 min. Following a 10 min recovery period in air, pups were returned and raised by their dam until weaning on PD21. Mice on PD84 (early adulthood) were sacrificed. The protein expression level of PFC were analysed by Western Blot and ELISA kit (Enzyme-Linked ImmunoSorbent Assay). RESULTS: We found increased expression levels of HIF-1α, NFκB and caspase-3 in the hypoxia induced mice when compared with the age-matched normoxic controls. We also found that level of IL-6 was increased in brain homogenate but not in the serum. DISCUSSION: These data suggest that obstetric complications in the form of perinatal hypoxia may lead to inflammation and apoptosis, which may contribute to increase risk of neurodevelopmental disorders such as schizophrenia/autism.