Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin.

Abstract

Neurotoxicity remains the most common adverse effect of oxaliplatin, limiting its clinical use. In the present study, we developed a mouse model of chronic oxaliplatin-induced neuropathy, which mimics both sensory and motor deficits observed in patients, in a clinically relevant time course. Repeated oxaliplatin administration in mice induced both cephalic and extracephalic long lasting mechanical and cold hypersensitivity after the first injection as well as delayed sensorimotor deficits and a depression-like phenotype. Using this model, we report that riluzole prevents both sensory and motor deficits induced by oxaliplatin as well as the depression-like phenotype induced by cumulative chemotherapeutic drug doses. All the beneficial effects are due to riluzole action on the TREK-1 potassium channel, which plays a central role in its therapeutic action. Riluzole has no negative effect on oxaliplatin antiproliferative capacity in human colorectal cancer cells and on its anticancer effect in a mouse model of colorectal cancer. Moreover, riluzole decreases human colorectal cancer cell line viability in vitro and inhibits polyp development in vivo. The present data in mice may support the need to clinically test riluzole in oxaliplatin-treated cancer patients and state for the important role of the TREK-1 channel in pain perception.

• Authors: Laura Poupon, Sylvain Lamoine, Vanessa Pereira, David A Barriere, Stéphane Lolignier, Fabrice Giraudet, Youssef Aissouni, Mathieu Meleine, Laëtitia Prival, Damien Richard, Nicolas Kerckhove, Nicolas Authier, David Balayssac, Alain Eschalier, Michel Lazdunski, Jérôme Busserolles
• Journal: Neuropharmacology (Neuropharmacology) Vol. 140 Pg. 43-61 (09 15 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 30056126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Kcnk4 protein, mouse
• Potassium Channels
• Potassium Channels, Tandem Pore Domain
• potassium channel protein TREK-1
• Oxaliplatin
• Riluzole

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Depression (chemically induced, prevention & control)
• Humans
• Male
• Mice
• Mice, Knockout
• Neoplasms (drug therapy)
• Neurotoxicity Syndromes (prevention & control)
• Oxaliplatin (adverse effects, antagonists & inhibitors)
• Pain Measurement (drug effects)
• Peripheral Nervous System Diseases (chemically induced)
• Potassium Channels (genetics)
• Potassium Channels, Tandem Pore Domain (antagonists & inhibitors, metabolism)
• Riluzole (pharmacology)