TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism

Abstract

Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1.

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…By both genetic and pharmacological approaches, we showed that TRPA1 entirely mediates mechanical and cold hypersensitivity induced by oxaliplatin and cisplatin [146] in mice and rats. We confirmed [103] that TRPV4 mediates part of the mechanical hyperalgesia induced by paclitaxel [74], and we showed that TRPV4-resistant mechanical hyperalgesia was exclusively mediated by TRPA1 [103]. We also discovered that paclitaxel-induced cold allodynia was completely due to TRPA1 activation [103].…”

“…We confirmed [103] that TRPV4 mediates part of the mechanical hyperalgesia induced by paclitaxel [74], and we showed that TRPV4-resistant mechanical hyperalgesia was exclusively mediated by TRPA1 [103]. We also discovered that paclitaxel-induced cold allodynia was completely due to TRPA1 activation [103]. One final common pathway activated by the otherwise chemically heterogeneous group of molecules, such as chemotherapeutic agents, is the production of oxidative stress in different tissues and cells [147,148] and, through this effect they can potentially activate and/or sensitize the TRPA1 channel.…”

“…One final common pathway activated by the otherwise chemically heterogeneous group of molecules, such as chemotherapeutic agents, is the production of oxidative stress in different tissues and cells [147,148] and, through this effect they can potentially activate and/or sensitize the TRPA1 channel. Our recent works [103,146], however, indicated that oxaliplatin and paclitaxel do not directly gate TRPA1, as they do not cause any calcium response in primary culture of mouse or rat DRG neurons. However, Chinese hamster ovary (CHO) cells transfected with the mouse TRPA1 channel respond, with a glutathionesensitive intracellular calcium mobilization, upon challenge with oxaliplatin, whereas untransfected CHO cells do not.…”

“…Recently, our research group has disclosed the role of TRPA1 in models of CIPN [103,146]. By both genetic and pharmacological approaches, we showed that TRPA1 entirely mediates mechanical and cold hypersensitivity induced by oxaliplatin and cisplatin [146] in mice and rats.…”

“…Recent evidence has proposed a role for TRPV4 in mechanical allodynia in rodent models of CIPN [101][102][103]. In different models of painful peripheral neuropathy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4 [74].…”