Oxidative Stress

Free radicals, which are produced during normal oxidative metabolism as oxygen and adenosine diphosphate are converted to water and adenosine triphosphate in the electron transport chain, are overproduced during ischemia, particularly reperfusion. This pathologic state is termed "oxidative stress." Although an elegant antioxidant enzyme system—which includes superoxide dismutase, glutathione peroxidase, and catalase—normally reduces toxic free radicals, ultimately converting them to water, this system is immature in the newborn brain. Developmental changes in the activities of these enzymes are imbalanced, causing accumulation of hydrogen peroxide (a toxic intermediary) in the neonatal brain in the setting of ischemic injury (31). In addition, the newborn brain is rich in free iron and is thus more susceptible to nonenzymatic attack by free radicals. Therapies aimed against this form of toxicity appear to be promising (32). The generation of reactive nitrogen species also contributes to cell death after stroke, and the neonatal brain is uniquely susceptible because of its ability to produce nitric oxide in selectively vulnerable regions. One of the isoenzymes responsible for generation of reactive nitrogen species is neuronal nitric oxide synthetase (nNOS), which is maximally expressed in regions where the immature NMDA-R is expressed, especially the basal ganglia (33). When nitric oxide is produced in excessive amounts during periods of oxidative stress in these regions of abundance, it is converted to peroxynitrite, a potent mediator of free radical injury (34). nNOS-expressing neurons are resistant to both hypoxia-ischemia and NMDA-mediated excitotoxicity (35,36). However, intracranial pressure (ICP) thresholds to ameliorate secondary brain injury have differed in previous studies; but this resistance of striatal neurons to NMDA agonists is limited to young ages (< P7 in rodent), and as the brain matures, this resistance is lost (36). Therapies designed to reduce both nNOS and inducible nitric oxide synthase activity have proven beneficial in small and large animal models (37).

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