Inflammation and ischemia in the developing brain - modifying effects of hyperoxia and adrenoceptor activation

Sammanfattning: Inflammation and ischemia are common causes of perinatal brain damage. Ventilation with pure oxygen has previously been the prime choice during resuscitation following fetal asphyxia. In an in vivo sheep model incorporating the transition from fetal to neonatal life we demonstrate that hyperoxic resuscitation increases cerebral inflammatory activation which may aggravate subsequent injury. Inflammation and ischemia activate overlapping molecular mechanisms to promote neural cell death in the developing brain. In an in vitro hippocampal slice culture model of neonatal inflammation and ischemia we observe that lipopolysaccharide (LPS)-induced inflammation induces sensitization to subsequent in vitro ischemia, whereas a prolonged interval between the respective insults results in a preconditioning effect. Both sensitization and pre-conditioning are dependent on signaling through tumor necrosis factor receptor 1. The hypothesized neuro-protective effects of adrenoceptor (AR)-activation were evaluated in the previously characterized model of LPS-indcued inflammation and in vitro ischemia in hippocampal slices. Beta1AR-activation conferred potent neuro-protection which was associated with down-regulation of pro-inflammatory cytokine secretion as well as offering protection in pure in vitro ischemia indicating interference with excitoxic mechanisms. Mechanisms associated with the neuroprotective effects of beta1AR-activation were further investigated by genome wide expression analysis in hippocampal slices using microarray technology. Neuroprotection induced by beta1AR-activation was associated with an extensive down-regulation of pro-inflammatory genes and by activating cellular defence against oxidative stress and apoptosis. These resutls offer important insights in mechanisms involved in endogenous defence against cerebral inflammation and ischemia and may aid in neuroprotective drug discovery.