Acute retigabine‐induced effects on myelinated motor axons in amyotrophic lateral sclerosis

Autor: Boudewijn T. H. M. Sleutjes, Diederik J. L. Stikvoort García, Maria O. Kovalchuk, Jules A. A. C. Heuberger, Geert Jan Groeneveld, Hessel Franssen, Leonard H. van denBerg
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Pharmacology Research & Perspectives, Vol 10, Iss 4, Pp n/a-n/a (2022)
Druh dokumentu: article
ISSN: 2052-1707
87080141
DOI: 10.1002/prp2.983
Popis: Abstract Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease‐modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post‐dose excitability differences were modeled well by a hyperpolarizing shift of the half‐activation potential of slow potassium (K+)‐channels (till 2 mV). These findings verify that retigabine targets slow K+‐channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies.
Databáze: Directory of Open Access Journals
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