Effect of hyperoxia on cortical neuronal nuclear function and programmed cell death mechanisms

There is growing concern over detrimental neurologic effects to human newborns caused by increased inspired oxygen concentrations. We hypothesize that hyperoxia (FiO(2) > 0.95) results in increased high-affinity Ca2+-ATPase activity, Ca2+-influx, and proapoptotic protein expression in cortical neuronal nuclei of newborn piglets. Neuronal cerebral energy metabolism was documented by determining ATP and phosphocreatine levels. Neuronal nuclear conjugated dienes and fluorescent compounds were measured as indices of lipid peroxidation. High-affinity Ca2+-ATPase activity and ATP-dependent Ca2+-influx were determined to document neuronal nuclear membrane function. Hyperoxia resulted in increases in lipid peroxidation, high-affinity Ca2+-ATPase activity, ATP-dependent Ca2+- influx, and Bax/Bcl-2 ratio in the cortical neuronal nuclei of newborn piglets. We conclude that hyperoxia results in modification of neuronal nuclear membrane function leading to increased nuclear Ca2+-influx, and propose that hyperoxiainduced increases in intranuclear Ca(2+)activates the Ca2+/calmodulin- dependent protein kinase pathway, triggering increased CREB protein-mediated apoptotic protein expression in hyperoxic neurons.