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Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice

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Abstract

Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds—rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)—daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.

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Acknowledgments

This work was supported by FINEP research grant “Implantação, Modernização e Qualificação de Estrutura de Pesquisa da PUCRS” (PUCRSINFRA) # 01.11.0014-00 and PRONEM / FAPERGS grant 11/2037-9. The authors would like to thank Dr. Maria Martha Campos for her valuable critical advice. We thank Dr. Léder Leal Xavier for the use of the laboratory facilities.

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Authors and Affiliations

  1. Programa de Pós Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Tania E. Schwingel, Caroline P. Klein, Natalia F. Nicoletti & Fernanda B. Morrone

  2. Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Fernanda B. Morrone

  3. Laboratório de Patologia do Hospital São Lucas da PUCRS, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Tiago G. Lopes & Vinicius Duval da Silva

  4. Programa de Pós-Graduação em Ciências da Saúde, Laboratório de Nanotecnologia Aplicada a Saúde, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil

    Cristiana L. Dora & Gabriela Hadrich

  5. Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil

    Cláudia G. Bica

  6. Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, Porto Alegre, RS, 90619-900, Brazil

    Fernanda B. Morrone

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  1. Tania E. Schwingel
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  2. Caroline P. Klein
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  3. Natalia F. Nicoletti
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  9. Fernanda B. Morrone
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Correspondence to Fernanda B. Morrone.

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Tania E. Schwingel and Caroline P. Klein have contributed equally to this paper.

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Schwingel, T.E., Klein, C.P., Nicoletti, N.F. et al. Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice. Naunyn-Schmiedeberg's Arch Pharmacol 387, 837–848 (2014). https://doi.org/10.1007/s00210-014-0994-0

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