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

Abstract

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres¹. 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 sclerosis². We now report some encouraging results obtained with 4-aminopyridine (4AP), a substance which blocks the voltage-dependent potassium currents in squid giant axons³. 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 fibres¹, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels^4,5. On the other hand, ⁴AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves⁶, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre⁷, 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 syndrome⁸ and myasthenia gravis⁹.