Kim Annink

152 Chapter 7 levels can also lead to production of superoxide after birth because xanthine-oxidase levels also rise during hypoxia (29). After birth, several pathways are activated because of reoxygenation leading to an excessive production of free radicals and superoxide in HIE. The increased levels of hypoxanthine and xanthine-oxidase in combination with the extra supply of oxygen during reoxygenation lead to the activation of the xanthine-oxidase pathway (22,30-32). Xanthine-oxidase converts hypoxanthine and oxygen into uric acid and superoxide (5), see Figure 2. This inappropriate superoxide production reaches its peak within 30 minutes after birth and plays a central role in the activation of destructive molecular pathways (30-32). The superoxide-derived hydrogen peroxide interacts with pro-radicals such as NBPI resulting in the formation of the very toxic hydroxyl free radical (22). Also nitric oxide (NO), derived from an increased production of endothelial and neuronal nitric oxide synthase, reacts with superoxide to form the toxic compound peroxynitrite (ONOO - ) (22,27,33,34). These free radicals and toxic compounds will cause additional neuronal cell damage, but they also activate an inflammatory response leading to the formation of (pro)inflammatory cytokines from about 6-12 hours after birth onwards (22,35). The subsequent apoptotic activity and eventually down regulation of trophic factors also contribute to the neuronal cell injury and start about 12 to 24 hours after birth and can last for days and even weeks (22,36,37). Given this potential pivotal role of superoxide, acute reduction of superoxide formation on top of moderate hypothermia by allopurinol might lead to a reduction of brain damage after perinatal asphyxia.