Healthy nerve cells transmit information by conducting impulses along the lengths of their membranes. Impulses are carried by the movement of charged particles (ions) through cellular channels in the axonal membrane, the most prominent being positively charged sodium (Na+) and potassium (K+) ions. This process is facilitated by the myelin sheath, which acts as an insulator to expedite impulse transmission. Myelin is often destroyed by the injury, although nerve axons may remain intact, and so several therapeutic strategies take aim at the surviving axons by endowing them with the capacity to transmit impulses in the absence of myelin (Chudler, 2004).
One approach is to transplant cells capable of myelination into demyelinated lesions (Kocsis et al., 2002, 2004). Several studies with animal models of spinal cord injury have provided evidence that implanted Schwann cells (cultured and purified) can remyelinate demyelinated axons, restore conduction, and improve function (Bunge and Wood, 2004).
Restoration of functional conduction across the membrane is still possible, without myelin, by altering channel activity. The drug 4-aminopyridine (fampridine) has been found to be effective in improving conduction in demyelinated axons in animal models (Shi and Blight, 1997). However, the results obtained with a sustained-release form of the drug in human clinical trials have been only modest. One trial showed negative results (van der Bruggen et al., 2001), but other small trials showed some improvements in individuals’ motor function and sensory function (pinprick and light touch) and reductions in spasticity (muscle tone) and pain (Qiao et al., 1997; Potter et al., 1998). The results for the two primary end points—spasticity and global impression of functioning—of the largest and most recent clinical trial (a phase III trial) did not reach statistical significance, according to the sponsor’s website (the results are not yet published). The study did show, however, a positive trend toward less spasticity (Acorda Therapeutics, 2004; Hayes et al., 2004).
Another therapeutic approach is to target sodium channels in a subtype-specific manner. When axons within the spinal cord are demyelinated, as in individuals with multiple sclerosis, the body inserts new sodium channels into the membrane of axons that have lost their myelin (Craner et al., 2004a,b). This is one example of plasticity, the body’s natural way of trying to adapt to changed conditions and compensating for lost function. Plasticity is not always beneficial, however. Neurons have 10 distinct sodium channels, each of which has different physiological properties. This represents a subtlety of neuronal design that permits different types of neurons to produce different patterns of impulses within the nervous system (Waxman, 2000). Some types of channels produce background levels of activity that can be interpreted by the brain as pain, whereas