Oxidative stress mediates thalidomide-induced pain by targeting peripheral TRPA1 and central TRPV4

Francesco De Logu,Ilaria Maddalena Marone,Serena Materazzi,Diéssica Padilha Dalenogare,Daniel Souza Monteiro De Araujo,Lorenzo Landini,Matilde Marini,Gabriela Trevisan,Pierangelo Geppetti,Mustafa Titiz,Simone Li Puma,Gaetano De Siena,Romina Nassini,Elisabetta Coppi

doi:10.1186/s12915-020-00935-9

Francesco De Logu, Ilaria Maddalena Marone + Show 12 more

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https://doi.org/10.1186/s12915-020-00935-9

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Abstract

BackgroundThe mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models.ResultsHere, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia.ConclusionsTargeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.

Highlights

The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood
We found that oxidative stress generated in peripheral tissues targets Transient receptor potential ankyrin 1 (TRPA1) to signal cold allodynia, and part of the mechanical allodynia, whereas oxidative stress generated in the central nervous system (CNS) targets central TRP vanilloid 4 (TRPV4) to mediate the TRPA1-resistant component of mechanical allodynia
Thalidomide evokes mechanical and cold hypersensitivity mediated by TRPA1 and TRPV4 To explore whether thalidomide elicited sensory hypersensitivities in mice, we administered a single i.p. injection of increasing doses (1, 10, 50, and 100 mg/kg) of the drug, or its vehicle, in C57BL/6J mice

Summary

Introduction

The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Like other chemotherapeutics, the anticancer action of thalidomide is associated with the development of a painful peripheral neuropathy that may result in delay or even premature termination of an otherwise successful treatment [4]. The thalidomide derivatives, lenalidomide and pomalidomide, have been reported to cause painful neuropathy [5, 6]. To the best of our knowledge, there are no established animal models of thalidomide-induced neuropathy which reproduce painful responses in rodents, mimicking those that they cause in patients

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