title: An oral NaV1.8 blocker improves motor function in mice completely deficient of myelin protein P0.
abstract: Mice deficient of myelin protein P0 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 NaV1.8 on motor axons. We reported that in P0+/-, a model of CMT1B, the membrane dysfunction could be acutely improved by a novel oral NaV1.8 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 P0-/-, 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 P0-/- 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 P0-/- could be acutely improved by C31. This provides proof-of-concept that treatment with oral subtype-selective NaV1.8 blockers could be used to improve the motor function in severe forms of demyelinating CMT.
authors.affiliation: Department of Neuroscience and Pharmacology, Copenhagen University, Denmark.
authors.forename: Mette R
authors.initials: MR
authors.lastname: Rosberg
authors.affiliation: Department of Neuroscience and Pharmacology, Copenhagen University, Denmark.
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: Department of Neuroscience and Pharmacology, Copenhagen University, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Krarup
authors.affiliation: Department of Neuroscience and Pharmacology, Copenhagen University, Denmark; Department of Clinical Neurophysiology, The Neuroscience Center, Copenhagen University Hospital (Rigshospitalet), Denmark. Electronic address: moldovan@sund.ku.dk.
authors.forename: Mihai
authors.initials: M
authors.lastname: Moldovan
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects; D018993:Myelin P0 Protein / Q000235:genetics* / Q000378:metabolism; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D018993:Myelin P0 Protein; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D026941:Sodium Channel Blockers
keywords: Charcot-Marie-Tooth disease; Conduction failure; Myelin protein P(0); Nerve excitability; Voltage-gated sodium channels