TABLE 5-2 Strategies to Block Cell Death

  • Block formation of free radicals

  • Block key proteases (e.g., caspases and calpain)

  • Block cytochrome c release

  • Block glutamate receptors

  • Promote adequate circulation

  • Combination (multipotential) therapies

 

SOURCE: Dobkin and Havton, 2004.

reducing ischemia (from the onset of injury), some are aimed at later events, and some are aimed at more than one event.

An emerging strategy, based on more than a decade of study with animal models, takes aim at the formation of free radicals, a crucial step in the onset of necrosis and apoptosis (see the next section) (Table 5-2) (Sugawara and Chan, 2003). Parallel lines of research on stroke and other neurological conditions are being conducted, with opportunities for collaborative efforts.

Control of Inflammation or Enhancement of Protective Immunity

The immune system’s response to injury has both protective and damaging effects, depending on the cell type, location, and concentration; the timing of the injury; and a host of other factors. One strategy that has been examined is to boost the protective effects of the immune system by injecting animals with T cells that inhibit a protein found in myelin (Hauben et al., 2000). This strategy was found to result in the death of fewer nerve cells. In another attempt to strengthen the immune response, macrophages were implanted into rats at the site of the lesion and distally into the parenchyma (Rapalino et al., 1998). The macrophages were derived from fractions of blood enriched with peripheral blood monocytes incubated with segments of sciatic nerve. Rats injected with the activated macrophages showed improved axon regrowth and motor function. A clinical trial based on the results of the work by Rapalino and colleagues was then initiated (Bomstein et al., 2003; Proneuron Biotechnologies, 2004), and a multisite phase II clinical trial is now being conducted; the results have not yet been published.

One contrasting strategy—to blunt the damaging effects of the immune system—is potentially possible with immunosuppressant drugs, such as cyclosporin A and FK506 (tacrolimus). Transplant surgeons have used immunosuppressants to prevent organ rejection for many years, and in recent years these agents have successfully been used as neuroprotective agents in



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