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

被引：50

作者：

Poupon, Laura ^{[1
,2
]}

Lamoine, Sylvain ^{[1
,2
]}

Pereira, Vanessa ^{[1
,2
]}

Barriere, David A. ^{[1
,2
]}

Lolignier, Stephane ^{[1
,2
]}

Giraudet, Fabrice ^{[1
,2
]}

Aissouni, Youssef ^{[1
,2
]}

Meleine, Mathieu ^{[1
,2
]}

Prival, Laetitia ^{[1
,2
]}

Richard, Damien ^{[1
,2
]}

Kerckhove, Nicolas ^{[1
,2
]}

Authier, Nicolas ^{[1
,2
]}

Balayssac, David ^{[1
,2
]}

Eschalier, Alain ^{[1
,2
]}

Lazdunski, Michel ^{[3
,4
]}

Busserolles, Jerome ^{[1
,2
]}

机构：

[1] Univ Clermont Auvergne, CHU Clermont Ferrand, INSERM, Neurodol, F-63000 Clermont Ferrand, France

[2] Inst Analgesia, Fac Med, BP38, F-63001 Clermont Ferrand, France

[3] Univ Nice Sophia Antipolis, F-06560 Valbonne, France

[4] CNRS, UMR 7275, Inst Pharmacol Mol & Cellulaire, 660 Route Lucioles Sophia Antipolis, F-06560 Valbonne, France

来源：

NEUROPHARMACOLOGY | 2018年 / 140卷

关键词：

Oxaliplatin; TREK-1 potassium channel; Riluzole; Neurotoxicity; Prevention; Colorectal cancer; MULTIPLE INTESTINAL NEOPLASIA; SPINAL-CORD; K+ CHANNEL; PERIPHERAL NEUROPATHY; GLUTAMATE RELEASE; PAIN; ISCHEMIA; MECHANO; COLD; CANCER;

D O I：

10.1016/j.neuropharm.2018.07.026

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 anti proliferative 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. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：43 / 61

页数：19

共 77 条

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