(ROCK), an enzyme that appears to dismantle the cell’s internal scaffolding necessary for the growing tip of the axon (Amano et al., 2000). By inhibiting its destructive action, researchers believe that they can prevent the collapse of the growing tip and thus promote axonal extension. A phase I/II clinical trial is currently under way to evaluate the safety, pharmacokinetics, and efficacy of an antagonist to ROCK, Cethrin, in promoting neurogeneration and neuroprotection.

Promotion of Axon Regrowth and Guidance

For most of the last century, the dogma was that regrowth of nerve axons occurred only in the peripheral nervous system and not in the CNS. Landmark experiments in the early 1980s revolutionized thinking about nerve cells’ capacity for long-distance regeneration. The experiments showed that CNS axon regrowth and connectivity could occur if the CNS environment was changed to match that normally present in peripheral nerves (David and Aguayo, 1981; Keirstead et al., 1989). The previous section highlighted techniques used to overcome the inhibitory environment. This section highlights the axon itself and what treatments might directly boost its regrowth. In reality, the distinction between eliminating the inhibitory effects of glial cells and promoting axon regrowth is blurred, and the techniques are closely intertwined.

The promotion of axon regrowth depends, first, on saving the entire neuron from apoptotic cell death (see above). Survival of the whole cell and then promotion of axon regrowth depend on the presence of growth factors in the immediate environment. The majority of these projections remain very short and local to the immediate site of injury. For unknown reasons, however, some fibers are capable of growing long distances around the lesion site. Nevertheless, axon regrowth does not result in improved function unless the axons can stimulate and inhibit the correct cellular target, whether it is in the brain, the spinal cord, or the periphery. If incorrect synapses are formed, pain and spasticity rather than restoration of normal walking and other functions can ensue.

Axon regrowth can also be stimulated by a variety of growth factors and other agents that enhance growth. Agents found to be successful in animal models are the purine nucleotide inosine (Benowitz et al., 1999) and cyclic AMP (Neumann et al., 2002; Qiu et al., 2002). Elevation of cyclic AMP levels by prevention of its normal breakdown can also induce regrowth (Pearse et al., 2004). Whether these agents work directly on the growing tip or more indirectly through the cell’s nucleus is not fully known.

Axon regrowth may be necessary, but not sufficient, to regenerate a functional neuronal circuit capable of controlling movements or responding to stimuli. It is also critical that the regrowing axons find their correct



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