Minimizing oxidative injury to the developing brain: the therapeutic quest continues

Abstract

EDITOR-IN-CHIEF Oxidative injury to the developing central nervous system continues to be an area of concern and controversy in perinatal medicine. The clinical examples of hypoxia‐ ischemia-induced oxidative stress in the perinatal period include antepartum and intrapartum asphyxial events and neonatal respiratory distress. In the last scenario, oxidative stress may also be produced during resuscitation secondary to hyperoxygenation. The spectrum of oxidative stress-induced neurological syndromes extends from behavioral and learning disabilities to cerebral palsy. However, the causal relationship between clinically recognized episodes of hypoxia and perinatal brain lesions is often uncertain. Most cases of perinatal neurological compromise do not demonstrate any defined antecedents and most cases of perinatal asphyxia do not result in any demonstrable neurodevelopmental deficit. These controversies reflect deficiencies in our knowledge in this field. Recent investigations, however, have made significant contributions to the elucidation of this complex problem, especially in the underlying molecular mechanisms 1 . Hypoxia‐ ischemia-induced neuronal injury essentially starts with neuronal energy failure, resulting in the excessive production of both oxygen-free and other secondary radicals, and non-radical reactive species which can injure cell constituents. There is direct evidence of oxygen-free radical generation in the developing brain in response to hypoxia 2,3 . Cells generate oxygen-free radicals during normal respiratory and metabolic activities. Oxygen-free radicals are redox intermedates produced during the sequential reduction of oxygen to water, as an integral part of the energy-regenerating process of oxidative phosphorylation. Biologically significant examples of oxygen-free radicals include superoxide, hydroxyl, lipid hydroperoxide, lipid peroxyl and lipid alkoxyl radicals, and also nitric oxide. The non-radical intermediates include hydrogen peroxide and singlet oxygen. These radical and non-radical products are often collectively called reactive oxygen species. The mechanisms for the formation of these agents are complex and multiple, and include mitochondrial respiration and various metabolic pathways 4‐7 . Additional mechanisms of free radical generation in the brain include inflammatory and immunological reactions, expression of adhesion molecules, and stimulation of polymorphonuclear