Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation

Abstract

Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. We hypothesized that the transient receptor potential ankyrin 1 (TRPA1), a cation channel activated by oxidative stress and cold temperature, contributes to mechanical and cold hypersensitivity caused by oxaliplatin and cisplatin. Oxaliplatin and cisplatin evoked glutathione-sensitive relaxation, mediated by TRPA1 stimulation and the release of calcitonin gene-related peptide from sensory nerve terminals in isolated guinea pig pulmonary arteries. No calcium response was observed in cultured mouse dorsal root ganglion neurons or in naïve Chinese hamster ovary (CHO) cells exposed to oxaliplatin or cisplatin. However, oxaliplatin, and with lower potency, cisplatin, evoked a glutathione-sensitive calcium response in CHO cells expressing mouse TRPA1. One single administration of oxaliplatin produced mechanical and cold hyperalgesia in rats, an effect selectively abated by the TRPA1 antagonist HC-030031. Oxaliplatin administration caused mechanical and cold allodynia in mice. Both responses were absent in TRPA1-deficient mice. Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals.

Oxaliplatin-Induced Neuropathy: Oxidative Stress as Pathological Mechanism. Protective Effect of Silibinin

“…has been described for oxaliplatin in CHO cells. 34 As things stand today, direct data about oxidative damage induced in vivo by platin derivatives are however still lacking. Moreover, the absence of a clear oxidation target hampers the finding of more active antioxidant compounds.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…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.…”

“…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].…”

Effects of Hypericum perforatum extract on oxaliplatin-induced neurotoxicity: in vitro evaluations

“…The most common side effect of these drugs is chemotherapy-induced neuropathy which often leads to reduction or discontinuation of therapy [7]. Oxaliplatin is able to induce neuropathic pain through several mechanisms including the modulation of Na + channels [8], alteration in Ca 2 + homeostasis [7], production of oxygen reactive species [9] and increase in caspase-mediated apoptosis [10]. Among those, oxidative stress is a key pathological feature of neuropathic pain [11][12][13].…”