Brain, Vol. 123, No. 1, 171-184,
January 2000
© 2000 Oxford University Press
Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension
Neuroinflammation Research Group, Department of Neuroimmunology, Guy's, King's and St Thomas' School of Medicine, Guy's Campus, London SE1 9RT, UK
Correspondence to:
Kenneth J. Smith, Department of Neuroimmunology, Guy's, King's and St Thomas' School of Medicine, Guy's Campus, London SE1 9RT, UK E-mail: kenneth.smith{at}kcl.ac.uk
Several clinical trials have demonstrated that 4-amino-pyridine (4-AP), a potassium channel-blocking agent, improves symptoms in some patients with multiple sclerosis. The beneficial effects have typically been attributed to the restoration of conduction to demyelinated axons, since this effect was previously demonstrated experimentally. However, the clinical dose is ~250–1000 times lower than that used experimentally, potentially making extrapolation of the experimental findings unreliable. To examine the action(s) of 4-AP in demyelinating disorders, the drug was administered at clinical doses, both in vivo and in vitro, to rat dorsal column axons which had been experimentally demyelinated by the intraspinal injection of ethidium bromide. 4-AP had no consistent effect in restoring conduction to demyelinated axons, even to axons which were held just on the verge of conducting by adjusting the lesion temperature. However, 4-AP had prominent effects that did not involve demyelinated axons, including the potentiation of synaptic transmission and an increase in skeletal muscle twitch tension. We propose that these latter effects may be largely responsible for the beneficial action of 4-AP in multiple sclerosis patients. If so, the dominant effects of 4-AP in multiple sclerosis patients are independent of demyelination, and it follows that 4-AP may be beneficial in other neurological disorders in which function is diminished.
potassium channels; multiple sclerosis; demyelinating disease; symptomatic therapy; spinal cord injury
4-AP = 4-aminopyridine; CAP = compound action potential; DRR = dorsal root reflex; EBr = ethidium bromide; RPT = refractory period of transmission
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