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.

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…Moreover, riluzole decreases the viability of a human colorectal cancer cell line in vitro and inhibits polyp development in vivo. These data confirm the important role of TREK-1 and TRAAK in CIPN [82,83].…”

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

“…They will be revised with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the neuroprotective approach. In OHP-treated animals, riluzole prevents the excessive accumulation of glutamate [34], and recently it was evidenced the benefit of riluzole for sensorimotor and painful disorders of the peripheral nervous system, preventing OHP-induced peripheral nerve functional and morphological alterations, as well as related OHP-induced comorbidities [35]. It has been postulated that riluzole could exert its neuroprotective action through interaction with potassium channels of the K2P family (TREK, TRAAK) [36,37].…”

Role of TREK-1 in Health and Disease, Focus on the Central Nervous System

“…Intrathecal injection of miR-183 alleviated pain in rat model of CCI and downregulated TREK-1 expression (Shi et al, 2018). Recently, it was reported that TREK-1 modulator riluzole prevents both sensory and motor deficits in neuropathic pain induced by the chemotherapy drug oxaliplatin (Poupon et al, 2018). Nevertheless, conclusions drawn by this paper are not totally convincing because authors only consider riluzole as an activator and do not take into account its inhibitory effects.…”