Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger a-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or a-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress byproducts in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists. Cancer Res; 73(10); 3120-31. Ó2013 AACR.

Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain

“…This is a plausible suggestion, as TRPA1-immunoreactive fibers are expressed in human peripheral nerves (41). Chemotherapeutic drugs increase oxidative stress, which may result in pain hypersensitivity following activation of TRPA1 and TRPV4 channels located on sensory neurons (36,43,44). Indeed, TRPV4 and TRPA1 receptor antagonists show good efficacy at preventing and attenuating oxaliplatin-and paclitaxel-induced neuropathic pain (36,43).…”

“…In order to evaluate whether monocyte-macrophages produce pronociceptive mediators, we tested whether shed FKN induced production of pronociceptive reactive oxygen species (ROS), known to activate TRPA1 channels on the terminals of sensory neurons in sciatic nerve and evoke a pain response (33)(34)(35). Oxidative stress occurs during chemotherapy treatment, and TRPA1 receptors are an attractive pain target, as their antagonists attenuate established chemotherapy-induced mechanical and thermal hypersensitivity (36)(37)(38). Here, we observed that systemic treatment with the antioxidant acetyl-l-carnitine during the first VCR cycle significantly attenuated the development of allodynia by approximately 50% (Figure 6A), confirming the role of oxidative stress in the VCR model.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Geppetti and co-workers recently explored the role of TRPA1 in rodent CIPN models (Nassini et al, 2011;Materazzi et al, 2012;Trevisan et al, 2013). They showed that TRPA1 entirely mediates both the mechanical and cold hypersensitivity that develops in mice and rats in response to oxaliplatin and cisplatin administration.…”

Paclitaxel inhibits mRNA transport in axons

“…From then on the time was measured until they elevate the paw and try to remove the acetone. The measurements were performed up to 60 s and repeated three times in 10-15 min intervals as previously described (Trevisan et al, 2013).…”