An oral NaV1.8 blocker improves motor function in mice completely deficient of myelin protein P0

Mice deficient of myelin protein P-0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform Na(V)1.8 on motor axons. We reported that in P-0+/-, a model of CMT1B, the membrane dysfunction could be acutely improved by a novel oral Na(V)1.8 blocker referred to as Compound 31 (C31, Bioorg. Med. Chem. Lett. 2010, 20, 6812; AbbVie Inc.). The aim of this study was to investigate the extent to which C31 treatment could also improve the motor axon function in P-0-/-, a CMT model with a much more severe neuropathy. We found that the progressive impairment of motor performance from 1 to 4 months of age in P-0-/- could be acutely reversed by C31 treatment. The effect was associated with an improvement of the amplitude of the plantar CMAP evoked by tibial nerve stimulation. The corresponding motor nerve excitability studies by threshold tracking showed changes after C31 consistent with attenuation of a resting membrane depolarization. Our data suggest that the depolarizing motor conduction failure in P-0-/- could be acutely improved by C31. This provides proof-of-concept that treatment with oral subtype-selective Na(V)1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT. (C) 2016 Elsevier Ireland Ltd. All rights reserved.