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Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes

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Abstract

Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.

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Acknowledgements

This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil (Grant Number 470252/2013-8). L. M. Pereira, S. D. C. Rodrigues, and H. Q. S. Aguiar are fellows from the Institutional Program of Scientific Initiation Scholarships of the Universidade Federal do Tocantins (PIBIC/CNPq/UFT). We would like to thank Editage (www.editage.com) for English language editing.

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  1. Programa de Pós-Graduação em Sanidade Animal e Saúde Pública nos Trópicos, Universidade Federal do Tocantins, BR-153, km 112, Araguaína, TO, 77804-970, Brazil

    Rita de Cássia Noronha Medeiros, Juliana Oliveira Moraes & Fabiano Mendes de Cordova

  2. Curso de Medicina Veterinária, Universidade Federal do Tocantins, BR-153, km 112, Araguaína, TO, 77804-970, Brazil

    Samara Dias Cardoso Rodrigues, Leidiano Martins Pereira, Helen Quézia da Silva Aguiar & Alberto Yim Júnior

  3. Curso de Medicina, Universidade Federal do Tocantins, Av. Dionísio Farias, 838, Araguaína, TO, 77814-350, Brazil

    Clarissa Amorim Silva de Cordova

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  1. Rita de Cássia Noronha Medeiros
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Contributions

All listed authors meet the requirements for authorship. RCNM, AYJr, CASC and FMC conceived and designed the experiments; RCNM, JOM, LMP, SDCR, HQSA and FMC performed the experiments. RCNM, AYJr, CASC and FMC performed the experiments and wrote the main manuscript text. All authors have read and approved the manuscript.

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Correspondence to Fabiano Mendes de Cordova.

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Conflict of interest

The authors do not have any financial or personal relationships that could inappropriately influence or bias the content of the paper.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Universidade Federal do Tocantins Ethics Committee on Animal Use, CEUA-UFT, Permit Number 23101.000284/2014-13).

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Medeiros, R.C.N., Moraes, J.O., Rodrigues, S.D.C. et al. Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes. Neurochem Res 45, 940–955 (2020). https://doi.org/10.1007/s11064-020-02975-7

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