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Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+—ATPase, Oxidative Stress, and 7-Chloro-4-(phenylselanyl) quinoline Therapy

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Abstract

Almost 90% of patients develop pain immediately after oxaliplatin (OXA) treatment. Here, the impact of aging on OXA-induced acute peripheral neuropathy and the potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) as a new therapeutic strategy were evaluated. In Swiss mice, the oxidative damage and its influence on Mg2+—ATPase and Na+, K+—ATPase activities were investigated. The relationship between the reactive oxygen species (ROS) and nitrate and nitrite (NOx) levels, the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) with the development of OXA-induced acute peripheral neuropathy was also studied. In this study, it was evidenced that OXA-induced acute peripheral neuropathy was exacerbated by aging through increased oxidative damage as well as Na+, K+—ATPase, and Mg+2—ATPase inhibition. 4-PSQ reversed hypersensitivity induced by OXA and aging-aggravated by reducing ROS and NOx levels, through modulation of GPx and SOD activities. 4-PSQ partially reestablish Na+, K+—ATPase activity, but not Mg 2+—ATPase activity. Locomotor and exploratory activities were not affected. This study is the first of its kind, providing new insight into the aging impact on mechanisms involved in OXA-induced acute peripheral neuropathy. Also, it provides evidence on promising 4-PSQ effects on this condition, mainly on aging.

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All data generated or analyzed during this study are included in this published article.

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Abbreviations

4-PSQ:

7-Chloro-4-(phenylselanyl) quinoline

OXA:

Oxaliplatin

NMDA:

N-Methyl-D-aspartate

ROS:

Reactive oxygen species

GPx:

Glutathione peroxidase

SOD:

Superoxide dismutase

NOx:

Nitrate and nitrite

CNS:

Central nervous system

NADPH:

β-Nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

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Funding

This study received financial support and scholarships from the following Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (429859/2018–0, 312747/2020–9), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (PqG 17/2551–0001013-2). This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível superior – Brasil (CAPES)—Finance Code 001. C.L.; E.A.W.; D.A. are recipients of CNPq fellowship. This study also received financial assistance from L’ORÉAL-UNESCO-ABC for Women in Science.

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Bioquímica E Bioprospecção (PPGBBio), Laboratório de Pesquisa Em Farmacologia Bioquímica, Centro de Ciências Químicas, Farmacêuticas e de Alimentos CCQFA, Universidade Federal de Pelotas, UFPel, Campus Capão do Leão, RS, CEP 96010-900, Pelotas, Brasil

    Angélica S. Reis, Carolina C. Martins, Ketlyn P. da Motta, Jaini J. Paltian, Cristiane Luchese & Ethel Antunes Wilhelm

  2. Programa de Pós-Graduação Em Química, Laboratório de Síntese Orgânica Limpa, CCQFA , Universidade Federal de Pelotas, UFPel, RS, CEP 96010-900, Pelotas, Brasil

    Gabriel P. Costa & Diego Alves

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  1. Angélica S. Reis
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  2. Carolina C. Martins
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  3. Ketlyn P. da Motta
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  7. Cristiane Luchese
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Contributions

A.S.R., C.C.M., K.P.M, J.J.P., C.L., and E.A.W. conceived and designed the study. G.P.C. and D.A. performed the 4-PSQ synthesis. A.S.R. and E.A.W. wrote the manuscript. E.A.W. supervised the study. All authors approved the final version of the manuscript.

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Correspondence to Cristiane Luchese or Ethel Antunes Wilhelm.

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Animal care and all experimental procedures were conducted in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH publications no. 80–23, revised in 1996). Also, this study was performed in line with the principles of the Declaration of Helsinki and in accordance with the Committee on Care and Use of Experimental Animal Resources, Federal University of Pelotas, Brazil (CEEA 4506–2017). All efforts were made to minimize the number of animals used and their suffering.

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Reis, A.S., Martins, C.C., da Motta, K.P. et al. Interface of Aging and Acute Peripheral Neuropathy Induced by Oxaliplatin in Mice: Target-Directed Approaches for Na+, K+—ATPase, Oxidative Stress, and 7-Chloro-4-(phenylselanyl) quinoline Therapy. Mol Neurobiol 59, 1766–1780 (2022). https://doi.org/10.1007/s12035-021-02659-5

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