Treatment of myotonia congenita with retigabine in mice.

Abstract

Patients with myotonia congenita suffer from muscle stiffness caused by muscle hyperexcitability. Although loss-of-function mutations in the ClC-1 muscle chloride channel have been known for 25 years to cause myotonia congenita, this discovery has led to little progress on development of therapy. Currently, treatment is primarily focused on reducing hyperexcitability by blocking Na+ current. However, other approaches such as increasing K+ currents might also be effective. For example, the K+ channel activator retigabine, which opens KCNQ channels, is effective in treating epilepsy because it causes hyperpolarization of the resting membrane potential in neurons. In this study, we found that retigabine greatly reduced the duration of myotonia in vitro. Detailed study of its mechanism of action revealed that retigabine had no effect on any of the traditional measures of muscle excitability such as resting potential, input resistance or the properties of single action potentials. Instead it appears to shorten myotonia by activating K+ current during trains of action potentials. Retigabine also greatly reduced the severity of myotonia in vivo, which was measured using a muscle force transducer. Despite its efficacy in vivo, retigabine did not improve motor performance of mice with myotonia congenita. There are a number of potential explanations for the lack of motor improvement in vivo including central nervous system side effects. Nonetheless, the striking effectiveness of retigabine on muscle itself suggests that activating potassium currents is an effective method to treat disorders of muscle hyperexcitability.

• Authors: Chris Dupont, Kirsten S Denman, Ahmed A Hawash, Andrew A Voss, Mark M Rich
• Journal: Experimental neurology (Exp Neurol) Vol. 315 Pg. 52-59 (05 2019) ISSN: 1090-2430 [Electronic] United States
• PMID: 30738808 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• CLC-1 channel
• Carbamates
• Chloride Channels
• KCNQ Potassium Channels
• Membrane Transport Modulators
• Phenylenediamines
• ezogabine

Topics

• Action Potentials (drug effects)
• Animals
• Behavior, Animal (drug effects)
• Carbamates (therapeutic use)
• Chloride Channels (genetics, metabolism)
• In Vitro Techniques
• KCNQ Potassium Channels (drug effects)
• Membrane Potentials (drug effects)
• Membrane Transport Modulators (therapeutic use)
• Mice
• Muscle Contraction (drug effects)
• Muscle, Skeletal (drug effects)
• Myotonia Congenita (drug therapy, psychology)
• Phenylenediamines (therapeutic use)
• Psychomotor Performance (drug effects)