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DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine

Authors

  • Vanessa Kaefer,

    1. Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil
    2. Laboratório de Farmacologia e Toxicologia, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, ULBRA, Canoas, RS, Brazil
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  • Juliane Garcia Semedo,

    1. Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil
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  • Vivian Francília Silva Kahl,

    1. Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil
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  • Rafael Gomes Von Borowsky,

    1. Laboratório de Farmacologia e Toxicologia, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, ULBRA, Canoas, RS, Brazil
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  • Janaína Gianesini,

    1. Laboratório de Farmacologia e Toxicologia, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, ULBRA, Canoas, RS, Brazil
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  • Tarso Benigno Ledur Kist,

    1. Laboratório de Métodos, Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul,UFRGS, Porto Alegre, RS, Brazil
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  • Patrícia Pereira,

    1. Laboratório de Farmacologia e Toxicologia, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, ULBRA, Canoas, RS, Brazil
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  • Jaqueline Nascimento Picada

    Corresponding author
    1. Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil
    • Laboratório de Genética Toxicológica, Programa de Pós-Graduação em Genética e Toxicologia Aplicada, Universidade Luterana do Brasil, ULBRA, Av. Farroupilha 8001, Bairro São José, Canoas, RS, CEP: 92425-900, Brazil
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Abstract

Amantadine (AMA) is an uncompetitive antagonist of the N-methyl-d-aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF-1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg−1) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step-down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg−1 AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3-day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.

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