Increased TRPA1 functionality in the skin of rats and cancer patients following oxaliplatin treatment

Abstract

Chemotherapy-induced peripheral neuropathy is a debilitating pathology affecting a majority of patients who are being treated with specific cytostatic compounds including oxaliplatin. Various in vitro, ex vivo and in vivo preclinical experiments indicate that transient receptor potential ankyrin 1 (TRPA1) plays a crucial role in the symptomatology of chemotherapy-induced peripheral neuropathy. However, it is unclear whether oxaliplatin also modulates the TRPA1 functionality in the skin of rodents or patients. Here, we quantified the vasodilation after topical application of the TRPA1 agonist cinnamaldehyde in a rodent model of chemotherapy-induced peripheral neuropathy (male Sprague Dawley rats, aged 6 weeks) as well as on fingers of patients suffering from chronic chemotherapy-induced peripheral neuropathy after oxaliplatin treatment. Compared to vehicle-treated rats, a cumulative dose of oxaliplatin 32 mg/kg enhanced the vasodilation after cinnamaldehyde application on rat abdominal skin. Likewise, also in patients with chronic chemotherapy-induced peripheral neuropathy after oxaliplatin, the response to cinnamaldehyde was significantly higher compared to sex- and age-matched healthy controls. Thereby, this study is the first to translate the evidence of increased TRPA1 functionality in vitro or ex vivo in rodents to in vivo conditions in human. The increased TRPA1 functionality in patients with chronic chemotherapy-induced peripheral neuropathy does not only confirm the potential of TRPA1 as target to hit to provide efficacious analgesia, it also paves the way for additional patient stratification on a molecular level and possible treatment response prediction.