Abstract
BackgroundFlupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine’s clinical profile.Trial designTo investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT).MethodsThreshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm.ResultsFlupirtine (3-30 μM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.).ConclusionsClinical doses of flupirtine reduce the excitability of peripheral myelinated axons.Trial registrationClinicalTrials registration is NCT01450865.
Highlights
Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels
Kv7.2 is found at nodes of Ranvier in peripheral nerve [6] and in motoneurones in the spinal ventral horn [7], while Kv7.3 is expressed in myelinating Schwann cells [8]
The current study has examined the profile of action of the Kv7 channel activator flupirtine by examining its effects on peripheral myelinated axons at clinically achieved concentrations
Summary
Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine’s clinical profile. A group of compounds which might influence axonal excitability are synthetic activators of slow axonal Kv7 potassium channels, Five genes (KCNQ1-5) encode Kv7 subunits, each with 6 trans-membrane spanning domains, a P-loop and a conserved A-domain in the cytoplasmic C-terminal region. The synthetic Kv7 channel activator retigabine shifts the activation of myelinated axons in the hyperpolarizing direction [6] and reduces the electrical threshold of unmyelinated axons in human sural nerve [12]. Flupirtine increases the electrical threshold of myelinated axons in rat sural [13] nerve
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
