Oxidative stress, brain white matter damage andintrauterine asphyxia in fetal lambs

Abstract

In order to examine the role of oxidative stress in asphyxia-induced perinatal braindamage, near-term fetal lambs were subjected to umbilical cord occlusion for approximately 60 min until fetal arterial pH diminished to less than 6.9 and base excess to less than −20 meq/l. Thelevels of superoxide, hydrogen peroxide, glutathione (GSH) and thiobarbiturate-reactivesubstances (TBARS) within brain grey and white matter were determined at 72 h to correlatewith morphological changes. Although the topography and extent of brain damage variedsomewhat from case to case, ranging from focal infarction in grey or white matter to subtle andpatchy alterations of white matter, the telencephalic white matter appeared to bear the brunt ofdamage as compared to other regions. The parietal white matter, in particular was often the seatof early pathological changes that could be seen in isolation. These white matter changes wereaccompanied by significant increases in hydrogen peroxide and TBARS levels as compared tothose in grey matter. In another set of experiments, 8 different brain regions were assayed forTBARS, GSH and superoxide dismutase (SOD). A highly significant rise in the levels of TBARSwas again noted in the parietal and frontal white matter. SOD levels were higher in the frontal andparietal white matter, basal ganglia and cerebellum. Cerebral cortical and hippocampal neuronswere relatively unaffected until accompanied by more severe damage to grey and white matter atother sites. These results suggest that the developing telencephalic white matter appears to bemost vulnerable to the effects of intrauterine fetal asphyxia and that oxidative stress may be amajor contributing factor in the pathogenesis of perinatal hypoxic–ischemic encephalopathy.