Referenced in: none

Automatically associated channels: Kir6.2

Title: Perinatal brain injury.

Authors: R Berger, Y Garnier

Journal, date & volume: J Perinat Med, 2000 , 28, 261-85

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/11031697

Abstract
Perinatal brain damage in the mature fetus is usually brought about by severe intrauterine asphyxia following an acute reduction of the uterine or umbilical circulation. The areas most heavily affected are the parasagittal region of the cerebral cortex and the basal ganglia. The fetus reacts to a severe lack of oxygen with activation of the sympathetic-adrenergic nervous system and a redistribution of cardiac output in favor of the central organs (brain, heart and adrenals). If the asphyxic insult persists, the fetus is unable to maintain circulatory centralization, 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 Na+/K+ pump at the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through the voltage-dependent ion channels, down an extreme extra-/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases and endonucleases. During ischemia, besides the influx of calcium ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarization. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to preischemic levels in non-vulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein synthesis, therefore, appears to be an early indicator of subsequent neuronal cell death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions and an imbalance between the excitatory and inhibitory neurotransmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Interestingly, there is increasing evidence from recent clinical studies that perinatal brain damage is closely associated with ascending intrauterine infection before or during birth. However, a major part of this damage is likely to be of hypoxic-ischemic nature due to LPS-induced effects on fetal cerebral circulation. Knowledge of these pathophysiological mechanisms has enabled scientists to develop new therapeutic strategies with successful results in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of intravenous administration of magnesium or postischemic induction of cerebral hypothermia.