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pump activity and uptake of glutamate during ischemia, an ischemic like condition may have significant influence on both sodium, water, hemostasis and cytotoxic swelling, as well as neuronal survival. Glutamate neuro-toxicity not only affects neurons but also oligodendrocytes. Glutamate is immediately released after traumatic brain injury as is glycine, serine, aspartate and GABA. There are many substances that are being investigated to reduce the effects of glutamate. Glutamate neuro-toxicity not only occurs early in traumatic brain injury, but also may be responsible for delayed cell death (its increased concentration may be the result of later cell death). The glutamate receptor may be inhibited at many of its components. The glycine site of the NMDA receptor can be inhibited with kynurenate, which has been shown to improve outcome, as well as riluzole, which not only decreases glutamate release but also inhibits the sodium channels and lubeluzole, which prevents an increase in extra-cellular glutamate, therefore, decreasing glutamate activated nitric oxide sensitase pathways. Nitric oxide has been thought of as a second messenger and recently has been seen as a primary neuro-transmitter. Nitric oxide is immediately increased after traumatic brain injury and returns to baseline within two hours. Nitric oxide synthetase forms nitric oxide, which reacts to form oxygen free radicals and resultant cytotoxic edema. Nitric oxide itself is a free radical gas as well as a signaling molecule. It vasodilates, it increases cerebral blood flow and opens the blood brain barrier. Nitric oxide synthetase is of three known types, n-NOS (neuronal) produces ischemia, e-NOS (endothelium) vasodilates and decreases infarct, i-NOS (inducible) probably causes neuronal damage. A nonselective inhibitor of NOS causes no significant changes in outcome, however, if i-NOS and n-NOS are inhibited 30 minutes after occlusion in a rat model, there is less infarction. Inhibition of e-NOS worsens infarction. n-NOS also opens the blood brain barrier. At the moment of traumatic brain injury, there is an increase in i-NOS and COX-2 that leads to blood brain barrier monocyte infiltration and activation of the microglia. This monocyte infiltration and activation of microglia may or may not be deleterious.
Inflammation is initiated by neutrophils. Neutrophils clear the site of injury of infectious agents and debris and facilitate healing. Neutrophils also secrete myeloperoxidases, which form hydrogen peroxide and lead to hydroxy-radicals that destroy tissue. The neutrophil infiltration is maximal at 24 hours. The role of cellular inflammation is controversial. Leukopenia does not change outcome and may be deleterious, whereas others say that neutropenia reduces infarct volume and edema. There is an immediate inflammatory reaction after traumatic brain injury with leukocyte adherence and vascular leakage. Then this does not lead to irreversible death. The chemicals unlike the cellular constituents of inflammation, however, have been shown to lead to a poor outcome. Immediately after traumatic brain injury there is an (Continued on page 52)
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