Roles of Transient Receptor Potential Ankyrin 1 in Oxaliplatin-Induced Peripheral Neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN), characterized by symptoms of paresthesia, dysesthesia, numbness, and pain, is a common adverse effect of several chemotherapeutic agents, including platinum-based agents, taxanes, and vinca alkaloids. However, no effective prevention or treatment strategies exist for CIPN because the mechanisms underpinning this neuropathy are poorly understood. Recent accumulating evidence suggests that some transient receptor potential (TRP) channels functioning as nociceptors in primary sensory neurons are responsible for CIPN. In this review, we focus on the specific roles of redox-sensitive TRP ankyrin 1 (TRPA1), which was first reported to be a cold nociceptor, in acute cold hypersensitivity induced by oxaliplatin, a platinum-based agent, because it induces a peculiar cold-triggered CIPN during or within hours after its infusion. Oxaliplatin-induced rapid-onset cold hypersensitivity is ameliorated by TRPA1 blockade or deficiency in mice. Consistent with this, oxaliplatin enhances the responsiveness of TRPA1 stimulation, but not of TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), in mice and cultured mouse dorsal root ganglion neurons. These responses are mimicked by an oxaliplatin metabolite, oxalate. In human TRPA1 (hTRPA1)-expressing cells, oxaliplatin or oxalate causes TRPA1 sensitization to reactive oxygen species (ROS) by inhibiting prolyl hydroxylases (PHDs). Inhibition of PHD-mediated hydroxylation of a proline residue within the N-terminal ankyrin repeat of hTRPA1 endows TRPA1 with cold sensitivity by its sensing of cold-evoked ROS. This review discusses these findings and summarizes the evidence demonstrating that oxaliplatin-induced acute cold hypersensitivity is caused by TRPA1 sensitization to ROS via PHD inhibition, which enables TRPA1 to convert ROS signaling into cold sensitivity.

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

“…The results of the present experiment confirmed that in mice, similarly to humans, oxaliplatin induced cold allodynia-a core symptom of neuropathic pain caused by this cytotoxic drug. After a single dose of oxaliplatin, cold allodynia was persistent and it was maintained for at least 7 days, which is consistent with the previous reports (Furgała, Fijałkowski, Nowaczyk, Sałat, & Sałat, 2018;Han, Kuo, Nicholson, Corradinni, & Smith, 2018;Kono et al, 2013;Nakagawa & Kaneko, 2017;Sałat, Furgała, & Sałat, 2019;Sałat et al, 2017).…”

“…In this assay, the maximum observation time (i.e., cut‐off time) was 60 s. In our earlier experiments, we tested a broader temperature range—from 1 to 4°C (Furgała, Sałat, & Sałat, ) and cold allodynia was measured at various time points: 2, 3, 4, 6, 24 hr, 3, and 7 days after oxaliplatin. We found that the development of cold allodynia could be observed as early as 2 hr after oxaliplatin administration, which is consistent with the previously published data (Nakagawa & Kaneko, ). It has to be noted that at this time point, this effect was statistically significant only in mice tested at 2.5°C.…”

“…Earlier studies also confirmed that after a single dose of oxaliplatin, cold allodynia is stable for at least 7 days, and therefore, this period was involved in the in vivo testing Nakagawa & Kaneko, 2017). 4.…”

“…For all temperatures tested, early‐phase cold allodynia was fully developed 3 hr after oxaliplatin injection, so for further experiments that involved measurements of predrug latencies to pain reaction this time point was chosen. Earlier studies also confirmed that after a single dose of oxaliplatin, cold allodynia is stable for at least 7 days, and therefore, this period was involved in the in vivo testing (Furgała, Sałat, et al., ; Nakagawa & Kaneko, ). It is worth noting that although the device we use (hot/cold plate apparatus, Bioseb, France) is supplied with a thermo‐controller which enables to maintain the temperature constantly at the desired level, each day prior to the testing session, the temperature of the plate was carefully checked by using a thermocouple probe. We used one (type BM807) purchased from Brymen Technology Corporation (Taiwan), but any device of this type and precision can be used.…”

“…There is a large body of evidence showing that oxaliplatin induces two forms of neuropathy-acute and chronic (reviewed in Starobova & Vetter, 2017), and these two phases are thought to be mediated by distinct mechanisms: altered neuronal excitability, TRPA1 channel activation (Nakagawa & Kaneko, 2017), impaired calcium homeostasis-all involved mainly in the development of the early phase, and mitochondrial dysfunction, glial cell activation, oxidative stress, axon degeneration, neuroinflammation underlying the late one (Nakagawa & Kaneko, 2017;Sisignano et al, 2014;Starobova & Vetter, 2017). Therefore, the efficacy of analgesics used for pain relief in these two phases of CIPN might be also different (Furgała, Fijałkowski, et al, 2018;Sałat et al, 2019).…”