Possible mechanisms of neurotoxicity and dopamine-mediated injury in the newborn brain during hypoxia and posthypoxic reoxygenation

This study investigated the metabolic responses of the dopaminergic system during hypoxia and the mechanisms by which dopamine may contribute to hypoxia-induced metabolic stress and dysfunction in neonatal brain. Newborn piglets were chosen as models because the level of brain development in piglets is comparable to that of a term newborn. Hypoxic conditions causing measurable but reversible cellular stress were used, with the level and duration of the hypoxic insult being quantitated through the measurement of the cortical oxygen pressure using oxygen dependent quenching of phosphorescence. During cerebral hypoxia, extracellular dopamine levels in the striatum, as determined by in vivo microdialysis, increased with even small decreases in oxygen pressure. Thus there is no oxygen reserve in brain tissue to protect against dopamine turnover during decreased tissue oxygen levels. During posthypoxic reoxygenation, in vivo microdialysis measurements showed that there was an increase in hydroxyl radical levels in striatum of newborn piglets, and that this increase was partly abolished by depleting the brain of dopamine. Oxidation of excess extracellular dopamine may therefore be contributing to the pathogenesis of neuronal injury through the increased production of free radicals. Hypoxia followed by two hours of reoxygenation induced expression of hsp72 mRNA, a marker of cellular stress, in different regions of newborn brain. In dopamine depleted animals, the hypoxia-induced hsp72 mRNA expression was significantly reduced relative to the non-depleted group. Production of free radicals via dopamine oxidation could be promoting neuronal cellular stress and pathology and consequently triggering hsp72 mRNA expression. Hypoxia and posthypoxic reoxygenation also led to changes in the ligand binding properties of striatal D$\sb1$ and D$\sb2$ dopamine receptor subtypes, receptors which regulate cellular metabolism through a variety of second messenger pathways. Inhibition of nitric oxide synthase and activation of tranglutaminase occurred during hypoxia and posthypoxic reoxygenation, respectively. These two enzymes may have important roles in neuronal function including dopamine metabolism and transport. The data suggest that in newborn brain, increased striatal extracellular dopamine contributes significantly to the pathogenesis of hypoxic metabolic dysfunction and cellular injury