administration of PKC inhibitors to rats with spinal cord injuries improves axon regeneration and myelination (Sivasankaran et al., 2004). In another rodent model, researchers degraded CSPGs by administering an enzyme, chondroitinase ABC. Administration of this enzyme promoted the regrowth of axons from spinal cord neurons into grafts of peripheral nerve into the spinal cord (Yick et al., 2004) and growth of CNS axons from grafts of Schwann cells into the spinal cord (Chau et al., 2004). The enzyme treatment also improved locomotion and proprioception (Bradbury et al., 2002; Yick et al., 2004).

Schwab (2004) and colleagues pioneered another line of research with animal models that targets the inhibitory molecule Nogo-A, which is expressed on the surface of myelin-forming oligodendrocytes. In 1990, it had been shown that antibodies to Nogo-A led to the regrowth of injured axons over long distances (Schnell and Schwab, 1990). A decade later, after the gene for Nogo-A had been cloned, the researchers developed a safer and more focused strategy: production of large quantities of a partially humanized version of a fragment of the antibody in vitro and then injection of this new antibody as a pure reagent (Brosamle et al., 2000). The results of experiments with mice that lack the Nogo gene (a strategy known as gene knockout) examining axon regrowth and improved gait after injury have varied (Kim et al., 2003). However, experiments performed with rats have shown that injection of the Nogo antibody promotes long-distance axonal regeneration and functional regeneration (Brosamle et al., 2000). A clinical trial of the Nogo antibody is being planned.

Because Nogo-A and other inhibitory agents exert their effects through the Nogo receptor, a protein that sits on the external membrane of axons, blockade of the Nogo receptor is another potential way to boost regrowth. GrandPre and colleagues (2002) applied the small peptide NEP1-40 to the injured spinal cord. NEP1-40 binds to, but fails to activate, the Nogo receptor. Those investigators found that receptor blockade leads to substantial regrowth of the disrupted axons. Because Nogo-A and other inhibitory substances (e.g., myelin-associated glycoprotein) act through the same receptor, receptor blockade has the advantage of simultaneously inhibiting more than one inhibitory substance. A follow-up experiment successfully adapted NEP1-40 for injection up to 2 weeks after a spinal cord injury, with some recovery of locomotion (Li and Strittmatter, 2003).

A related strategy being explored would target Nogo inhibition at the growing tip of the axon. Once the Nogo receptor is activated, it works through several intermediate reactions within the cell, known as signaling pathways, to block axon regrowth. When researchers targeted one of those intermediate reactions, and thus interrupted the signaling pathway, they found axon regrowth and the recovery of function (Fournier et al., 2003). This treatment was with an agent that inhibited Rho-associated kinase