Pathophysiology of perinatal brain damage

Perinatal brain damage in the mature fetus is usually brought about by seve re intrauterine asphyxia following an acute reduction of the uterine or umb ilical circulation. The areas most heavily affected are the parasagittal re gion of the cerebral cortex and the basal ganglia. The fetus reacts to a se vere lack of oxygen with activation of the sympathetic-adrenergic nervous s ystem and a redistribution of cardiac output in favour of the central organ s (brain, heart and adrenals). If the asphyxic insult persists, the fetus i s unable to maintain circulatory centralisation, and the cardiac output and extent of cerebral perfusion fall. Owing to the acute reduction in oxygen supply, oxidative phosphorylation in the brain comes to a standstill. The N a+/K+ pump at the cell membrane has no more energy to maintain the ionic gr adients. In the absence of a membrane potential, large amounts of calcium i ons flow through the voltage-dependent ion channel, down an extreme extra-/ intracellular concentration gradient, into the cell. Current research sugge sts that the excessive increase in levels of intracellular calcium, so-call ed calcium overload, leads to cell damage through the activation of proteas es, lipases and endonucleases. During ischemia, besides the influx of calci um ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an e xcitatory neurotransmitter, is released from presynaptic vesicles during is chemia following anoxic cell depolarisation. The acute lack of cellular ene rgy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesi s returns to pre-ischemic levels in non-vulnerable regions of the brain, wh ile in more vulnerable areas it remains inhibited. The inhibition of protei n synthesis, therefore, appears to be an early indicator of subsequent neur onal cell death. A second wave of neuronal cell damage occurs during the re perfusion phase. This cell damage is thought to be caused by the post-ische mic release of oxygen radicals, synthesis of nitric oxide (NO), inflammator y reactions and an imbalance between the excitatory and inhibitory neurotra nsmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Kn owledge of these pathophysiological mechanisms has enabled scientists to de velop new therapeutic strategies with successful results in animal experime nts. The potential of such therapies is discussed here, particularly the pr omising effects of i.v. administration of magnesium or post-ischemic induct ion of cerebral hypothermia. (C) 1999 Elsevier Science B.V. All rights rese rved.