Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis
Sleutjes, Boudewijn T H M; Stikvoort García, Diederik J L; Kovalchuk, Maria O; Heuberger, Jules A A C; Groeneveld, Geert Jan; Franssen, Hessel; van den Berg, Leonard H
(2022) Pharmacology research & perspectives, volume 10, issue 4, pp. 1 - 7
(Article)
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
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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.
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Keywords: Amyotrophic Lateral Sclerosis/drug therapy, Axons/physiology, Carbamates, Humans, Motor Neurons, Phenylenediamines/pharmacology, mechanism of action, axonal excitability, computational modeling, target engagement, Neurology, Pharmacology, Toxicology and Pharmaceutics(all), Journal Article
ISSN: 2052-1707
Publisher: Wiley-Blackwell Publishing Ltd
Note: Funding Information: BTHMS and DLJSG are funded by the Netherlands ALS Foundation, MK received grants from European Federation of Neurological Societies and Prinses Beatrix Spierfonds. HF received grants from Prinses Beatrix Spierfonds. LHvdB received funding from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), and the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS‐CarE project), funded via the EU Joint Programme—Neurodegenerative Disease Research (JPND). Biogen funded the clinical trial from which the data of this work originates. Funding Information: LHvdB served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix Spierfonds and the Latran foundation. HF reports previous grants from Biogen and personal fees from Shire. JAACH and GJG report grants from Biogen. BTHMS and DLJSG are funded by the Netherlands ALS Foundation, MK received grants from European Federation of Neurological Societies and Prinses Beatrix Spierfonds. HF received grants from Prinses Beatrix Spierfonds. LHvdB received funding from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), and the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded via the EU Joint Programme—Neurodegenerative Disease Research (JPND). Biogen funded the clinical trial from which the data of this work originates. Funding Information: LHvdB served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix Spierfonds and the Latran foundation. HF reports previous grants from Biogen and personal fees from Shire. JAACH and GJG report grants from Biogen. Publisher Copyright: © 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
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