title: 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 α-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 α-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 by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists.
authors.affiliation: Graduate Program in Biological Sciences: Toxicological Biochemistry, Department of Chemistry, Center of Natural and Exact Sciences, Federal University of Santa Maria (UFSM), Santa Maria, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Camilla
authors.initials: C
authors.lastname: Fusi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Altomare
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
authors.forename: Maura
authors.initials: M
authors.lastname: Lodovici
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001897:Boronic Acids / Q000633:toxicity; D000069286:Bortezomib; D051379:Mice; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D011687:Purines / Q000494:pharmacology; D011719:Pyrazines / Q000633:toxicity; D000074025:TRPA1 Cation Channel; D008063:Thioctic Acid / Q000494:pharmacology; D050051:Transient Receptor Potential Channels / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D000970:Antineoplastic Agents; D001897:Boronic Acids; D009944:Organoplatinum Compounds; D011687:Purines; D011719:Pyrazines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D000069286:Bortezomib; D008063:Thioctic Acid