Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification.

Marianna Dionisi,Armando A Genazzani,Antonio Ferrer-Montiel,Guido Cavaletti,Asia Fernandez-Carvajal,Dmitry Lim,Laura Monza,Carla Distasi,Giulia Fumagalli,Annalisa Canta,Cristina Meregalli,Beatrice Riva,Federico Alessandro Ruffinatti

doi:10.3390/ijms21197164

Abstract

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.

Highlights

Chemotherapy-induced peripheral neurotoxicity remains a common side effect of several anticancer agents, including vinca alkaloids, taxanes, platinum derivatives, bortezomib, and thalidomide [1]
Modulation of the expression of neuronal ionic channels by antineoplastic drugs has been suggested as a common mechanism of chemotherapy-induced peripheral neuropathy [30,31]
The involvement of the thermo- and mechanosensitive TREK channels in OHP-induced peripheral neurotoxicity (OIPN) is well documented [2,18]. These studies have highlighted a downregulation of TREK channel expression in nociceptors 90 h after OHP injection in mice and have suggested that such alteration contributes to cold hyperalgesia, cool allodynia, and mechanical hypersensitivity

Summary

Introduction

Chemotherapy-induced peripheral neurotoxicity remains a common side effect of several anticancer agents, including vinca alkaloids, taxanes, platinum derivatives, bortezomib, and thalidomide [1]. Hyperpolarizing K+ two-pore domain (K2P) channels work as regulators of the excitability of primary afferent fibers, and of pain signaling by tuning the excitation elicited by several stimuli, including temperature [8,9,10] and mechanical forces [11]. In accordance with this idea, it has been proposed that all TREK-family channels (TREK-1, TREK-2, and TRAAK), which are widely expressed in dorsal root and trigeminal ganglia, are implicated in the mediation of cold hyperalgesia, cool allodynia, and mechanical hypersensitivity following the treatment with OHP [2,12]

Methods

Results

Conclusion