• Jonathan Paulo Agnes, Vitória Wibbelt Dos Santos, das NevesRaquel NascimentoRNLaboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil., Rosângela Mayer Gonçalves, Marina Delgobo, Carolina Saibro Girardi, Débora Denardin Lückemeyer, Marcella de Amorim Ferreira, Sérgio José Macedo-Júnior, Samantha Cristiane Lopes, Fernando Spiller, GelainDaniel PensDPCentro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil., MoreiraJosé Cláudio FonsecaJCFCentro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil., Rui Daniel Prediger, Juliano Ferreira, and Alfeu Zanotto-Filho.
• Laboratório de Farmacologia e Bioquímica do Câncer, Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.
• J Pain. 2021 Aug 1; 22 (8): 9961013996-1013.

AbstractChemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1β and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.

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