been a limited number of clinical trials that have examined this treatment, but they do appear to support the benefit of hypothermia. A 2003 review of all published laboratory experiments of induced hypothermia for the treatment of traumatic spinal cord injuries showed that it offers no benefit for severe injuries but does result in improvements in functional outcomes in individuals with mild to moderate traumatic spinal cord injuries (Inamasu et al., 2003). Induced hypothermia has also been demonstrated to provide functional improvement in rats with ischemic spinal cord injuries (Dimar et al., 2000).

SECONDARY INJURY

Rescue of Neural Tissue at Risk of Apoptotic Cell Death

Neurons near the site of injury may be spared during the acute phase of injury, but they are at risk of dying during the secondary phase. Thus, another target of therapies for spinal cord injuries is to suppress the wave of apoptotic cell death that expands the scope of injury well beyond its original site. Apoptosis involves a complex sequence of biochemical reactions launched inside the cell by a variety of signals, including excessive calcium influx (see Chapter 2). A range of strategies is being tested to prevent apoptosis, primarily in animal models. The strategies fall under the umbrella term neuroprotection, because their goal is to shore up the nervous system’s defenses against the cascade of biochemical threads. Some strategies (e.g., inhibition of free radicals) may block not only apoptosis but also necrosis (Kondo et al., 1997). To add to the complexity, the death of the cell can also lead to the death of an adjacent cell; for example, apoptosis of oligodendrocytes may also induce death of the neurons that they ensheath or adjacent astrocytes (Hulsebosch, 2002). Apoptosis depends heavily on caspases, a group of intracellular proteins that cleave and thereby disable other proteins. Of this group of proteins, caspase-3 and caspase-9 are thought to be dominant players in spinal cord injury-induced apoptosis (Eldadah and Faden, 2000). Inhibition of caspases may therefore be key to preventing apoptosis. Several clinical trials of caspase inhibitors for the treatment of other illnesses are under way (NIH, 2004).

Another protease, calpain, also plays a role earlier in the biochemical cascade that leads to spinal cord injury-induced apoptosis and thus represents another target for the treatment of spinal cord injuries. Calpain inhibition has successfully prevented neuron death in animal models of spinal cord injury (Ray et al., 2003). Finally, a drug already on the market, the antibiotic minocycline, may alleviate the impact of a spinal cord injury by inhibiting the release of cytochrome c (Teng et al., 2004), a molecule also associated with apoptosis (Di Giovanni et al., 2003).



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