the case of lipid peroxidation, for example, free radicals draw an electron from a lipid molecule, which in turn becomes less stable, thus launching a chain reaction that ultimately leads to lysis of the membrane and death by necrosis.

Delayed Calcium Influx

Although neurons require some intracellular calcium for their normal function, too much calcium is injurious because it activates damaging enzymes and destructive processes and can trigger the formation of free radicals. Some calcium enters neurons at the time of injury and contributes to the acute phase of damage. An additional influx of calcium is triggered by the acute injury and continues for hours afterwards. A particularly powerful mode of calcium influx within injured axons in white matter involves an initial inward leakage of sodium due to the acute injury, which drives the sodium-calcium exchanger to import damaging levels of calcium; this multistage cascade has been demonstrated within myelinated axons of the optic nerve (Stys et al., 1992b) and the spinal cord (Imaizumi et al., 1997). This delayed calcium influx is an important target for interventions because, by blocking it, it is possible to reduce the degree of secondary damage to myelinated spinal cord axons (Stys et al., 1992a).

Immune System Response

The inflammatory response to injury involves four major categories of immune cells: neutrophils, monocytes, microglia, and T-lymphocytes (Schnell et al., 1999; Bareyre and Schwab, 2003). The neutrophils are the first immune cells to arrive at the site of injury. They are recruited there from the circulatory system, especially by vascular endothelial cells, which up-regulate and express adhesion molecules on their cell membranes to help guide neutrophils to the site of injury. Once the neutrophils have entered the spinal tissue, they remove microbial intruders and tissue debris. This is accomplished in many ways, especially through the release of toxic molecules and antibacterial agents (e.g., myeloperoxidase). Neutrophils also release cytokines, proteases, and free radicals, all of which activate other inflammatory and glial cells for the inflammatory cascade that can ultimately lead to neuron injury or death. Cytokines, which are soluble proteins released by most types of inflammatory cells, act as signals between immune cells and carry out immune functions. Neutrophils are the initial dominant cells involved in the immune response.

Over the next 24 hours, microglia respond in earnest. Monocytes begin to enter from the circulatory system and, after they penetrate the spinal cord tissue, differentiate into macrophages. Microglia, on the other hand,



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