Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord

Abstract

Blockade of potassium channels with the drug 4-aminopyridine has been shown to effect recovery of action potential conduction in myelinated axons under a variety of pathological conditions, but the mechanism and significance of this phenomenon are not completely understood. This study examined the effects of a range of 4-aminopyridine concentrations on conduction in an experimental model of chronic spinal cord injury in guinea-pigs, using sucrose-gap recording from isolated spinal cord strips. The amplitude of the compound action potential increased in response to bath application of 4-aminopyridine, with a threshold between 0.5 and 1 μM and the peak response between 10 and 100 μm. Conduction was suppressed at concentrations of 1 and 10 mM. Uninjured white matter showed no effect on the compound potential of 4-aminopyridine below 1 mM, but there was a similar suppression at concentrations above 1 mM, accompanied by marked membrane depolarization. Peripheral nerve showed only slight action potential suppression and depolarization in the presence of 10 mM 4-aminopyridine. The sensitivity of injured axons to 1 μM 4-aminopyridine is consistent with the hypothesis that some beneficial effects of the drug seen in patients with spinal cord injury are related to improved conduction in myelinated axons, since cerebrospinal fluid levels of 4-aminopyridine should approach this concentration following clinical systemic doses, although it remains likely that synaptic effects also play a role. The blockade of action potential conduction produced by much higher levels of 4-aminopyridine in vitro is possibly a consequence of interference with the resting potential mechanism of the axon membrane, which appears to differ between central and peripheral nerve fibers.