Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The use of a potassium-blocking agent to prolong action potentials may seem surprising because we previously found tetraethylammonium chloride (TEA), another potassium blocker, ineffective on normal rat myelinated fibres, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels. On the other hand, 4AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre, might further resemble its unmyelinated terminals by responding to 4AP. In testing this hypothesis, we have found that both TEA and 4AP prolong action potentials of demyelinated and unmyelinated fibres, and both facilitate conduction in fibres blocked by demyelination. 4AP is effective at lower concentrations, and is the more promising for clinical use, as it has already been used with beneficial effects in the treatment of Eaton-Lambert syndrome and myasthenia gravis.