Cerebral Cortical Tissue Damage After Hemorrhagic Hypotension in Near-Term Born Lambs

Abstract

Hypotension reduces cerebral O 2 supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the cerebral cortex, as measured with electrocortical brain activity (ECBA), is related to cerebral cortical tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of cerebral cortical tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O 2 supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO 2 and NO 3 (NOx) in plasma, and cGMP in cortical brain tissue were determined in both conditions. CSF and brain tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of cerebral cortical damage. T he developing brain requires an adequate supply of oxygen and substrates for function and growth. In immature newborns, cerebral oxygenation and hemodynamics are easily disturbed because of the immaturity of various organ systems, e.g. pulmonary and cardiovascular systems. Sufficient cerebral O 2 supply is therefore frequently jeopardized in those infants. Hypotension may diminish or disrupt the cerebral blood flow (CBF), with a consequent reduction of the supply of oxygen and substrates to the brain, thereby hindering the brain in normal functioning and growth (1).Neurons are very sensitive to reduced supplies of oxygen and glucose (2,3). Reduced cerebral O 2 supply results in a cascade of events. The excess release of excitatory amino acids, in particular glutamate, during conditions of energy failure initiates a massive influx of Ca 2ϩ into the cell. The increased intracellular Ca 2ϩ concentration triggers Ca 2ϩ -dependent processes (4), such as the formation of NO from L-arginine by nitric oxide synthase (NOS) (5). NO increases the concentrations of cyclic GMP (cGMP) through the activation of soluble guanylate cyclase (sGC) (5). Ultimately, this cascade may lead to brain cell dysfunction and cell death (6). Whereas brain cell dysfunction can be measured in vivo noninvasively by neurophysiological methods (7,8), brain cell death can only be assessed histologically. Microtubuleassociated proteins (MAP) are a diverse family of cytoskeletal proteins apparently present in all ...

Cortical Excitatory Amino Acid Release and Cell Function during Hypotension in Near-Term Born Lambs

“…Moreover, high extracellular concentrations of glutamate contribute to the excitotoxic death of neurons [2,9,35] . Previously, we have demonstrated histologically that cortical tissue damage occurred after 2.5 h of reduced cerebral O 2 -supply due to hemorrhagic hypotension in the near-term born lamb [5] . The damage was accompanied by a reduction of ECBA.…”