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(Continued from page 51)
increase in CSF interleukon-6, but not CSF interleukon-10. Interleukon-6 is pro-inflammatory, whereas interleukon-10 is anti-inflammatory. There have been reported poor outcomes with increases in interleukon-6. Interleukon-1 messenger RNA, which is also pro-inflammatory, is also increased soon after traumatic brain injury, within one hour, and also has been shown to lead to poor outcome. Both dexamethasone and indomethacin inhibit cyclo-oxygenase, a component of inflammation.
Glutamate not only interacts with nitric oxide causing that cascade of changes, but also stimulates and is stimulated by calcium. Glutamate stimulates calcium influx that stimulates the membrane transporter sodium hydrogen ion anti-transporter, causing an influx of hydrogen ions and water. Intracellular calcium also activates the protease calpain, which causes proteolytic degradation. This peaks at one to two hours after traumatic brain injury. The intracellular increase in calcium after traumatic brain injury causes a change in the mitochondrial membrane, leading to impairment of the mitochondrial electron and energy transport capacities, uncoupling oxidative phosphorylation. The intracellular calcium increase after re-oxygenation, which is from both intracellular supplies initially, and extracellular supplies after re-oxygenation, stimulates second messenger systems, such as nitric oxide that eventually lead to cellular injury. This increase in intracellular influx is suppressed by PEG-SOD and indomethacin, but not by nimodipine. Calcium activation normally is a good thing, but like glutamate under traumatic and therefore neuro-toxic conditions, produces a variety of additional insults, which lead to cellular injury.
Glutamate also affects cellular metabolism. Glutamate stimulates astrocytic glucose uptake and without oxygen anaerobic respiration generates lactate, which cannot be used as an energy source under anaerobic conditions, and it accumulates. Not only is lactate generated, but also hyperglycolysis uses ATP, which leads to the accumulation of adenosine and inosine. Adenosine is the final product released when there is complete uncoupling of the cerebral blood flow, cerebral metabolism of oxygen and finally cell death. Adenosine can be measured in the cerebrospinal fluid. When the energy stores are depleted, the cellular membrane integrity collapses releasing additional glutamate and aspartate causing additional neurotoxic destruction. The anaerobic metabolism of glucose and lactate is independent of the cerebral blood flow, and leads to an increase in intracellular hydrogen ions. Red blood cells carry oxygen, they do not carry glucose, and the plasma carries glucose with only minimal oxygen. During ischemia there is a decreased flow in red blood cells, but continued flow of plasma. Therefore, glucose is delivered to the cell in the anaerobic condition. It is now believed that glucose administration causes additional problems after secondary injury, such as from increased intracranial pressure, hypotension and hypoxia. Under normal conditions, red blood cells (Continued on page 53)
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