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Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation

  • Jonathan Paulo Agnes
    Affiliations
    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
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  • Vitória Wibbelt dos Santos
    Affiliations
    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
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  • Raquel Nascimento das Neves
    Affiliations
    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
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  • Rosângela Mayer Gonçalves
    Affiliations
    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
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  • Marina Delgobo
    Affiliations
    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
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  • Carolina Saibro Girardi
    Affiliations
    Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
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  • Débora Denardin Lückemeyer
    Affiliations
    Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Marcella de Amorim Ferreira
    Affiliations
    Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Sérgio José Macedo-Júnior
    Affiliations
    Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Samantha Cristiane Lopes
    Affiliations
    Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Fernando Spiller
    Affiliations
    Laboratório de Imunobiologia (Lidi), Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Daniel Pens Gelain
    Affiliations
    Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
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  • José Cláudio Fonseca Moreira
    Affiliations
    Centro de Estudos em Estresse Oxidativo, Departamento de Bioquimica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
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  • Rui Daniel Prediger
    Affiliations
    Laboratório Experimental de Doenças Neurodegenerativas, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Juliano Ferreira
    Affiliations
    Laboratório de Farmacologia Experimental, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil
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  • Alfeu Zanotto-Filho
    Correspondence
    Address reprint requests to Alfeu Zanotto-Filho, PhD, Departamento de Farmacologia, Centro de Ciências Biológicas (CCB), Universidade Federal de Santa Catarina (UFSC) – Campus Trindade; Florianópolis, Santa Catarina (SC), Brazil. Zipcode: 88049-900.
    Affiliations
    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
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      Highlights

      • Antioxidants ameliorate OXA-induced peripheral neuropathy in tumor-bearing mice.
      • OXA promotes ROS production and inflammation in the spinal cord of mice.
      • Antioxidants abrogate ROS-induced spinal cord inflammation in OXA-treated mice.
      • Tlr4 knockout decreases spinal cord inflammation and mechanical allodynia.
      • Antioxidants do not impair the antitumor efficacy of OXA.

      Abstract

      Chemotherapy-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.

      Graphical abstract

      Key words

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