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Pre-treatment and continuous administration of simvastatin during sepsis improve metabolic parameters and prevent CNS injuries in survivor rats

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Abstract

Sepsis causes overproduction of inflammatory cytokines, organ dysfunction, and cognitive impairment in survivors. In addition to inflammation, metabolic changes occur according to the stage and severity of the disease. Understanding the role and place of metabolic disturbances in the pathophysiology of sepsis is essential to evaluate the framework of septic patients, predict the syndrome progress, and define the treatment strategies. We investigated the effect of simvastatin on the disease time course and on metabolic alterations, especially with respect to their possible consequences in the CNS of surviving rats. The animals of this study were weighed daily and followed for 10 days to determine the survival rate. In the first experiment, control or cecal ligation and puncture (CLP)-animals were randomized in 24 h, 48 h, and 10 days after septic induction, for bacterial load determination and quantification of cytokines. In the second experiment, control or CLP-animals were treated or not with simvastatin and randomized in the same three time points for cytokines quantification and assessment of their body metabolism and locomotor activity (at 48 h and 10 days), as well as the evaluation of cytoarchitecture and astrogliosis (at 10 days). The CLP-rats treated with simvastatin showed a reduction in plasma cytokines and improvement in metabolic parameters and locomotor activity, followed by minor alterations compatible with apoptosis and astrogliosis in the hippocampus and prefrontal cortex. These results suggest that the anti-inflammatory effect of simvastatin plays a crucial role in restoring energy production, maintaining a hypermetabolic state necessary for the recovery and survival of these CLP-rats.

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Data available on request from the authors.

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Acknowledgements

The authors thank Nadir Fernandes for the technical support and Dr. Klaus Hartfelder for his assistance with English language.

Funding

The study was funded by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-Grant 2017/12462–0) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES): Finance Code 001.

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Authors and Affiliations

  1. Department of Neurosciences and Behavioral Sciences of Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    Carlos Henrique Rocha Catalão, Nilton Nascimento Santos-Junior & Luis Henrique Angenendt da Costa

  2. Department of Chemistry, Institute of Exact and Earth Sciences, Federal University of Mato Grosso, Cuiabá, Brazil

    Anderson de Oliveira Souza

  3. Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    Jonathas Rodrigo dos Santos & Luciane Carla Alberici

  4. Department of Psychology, Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil

    Maria José Alves Rocha

  5. Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, CEP 14049-900, Brasil

    Carlos Henrique Rocha Catalão

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Contributions

CHRC and MJAR conceived and designed research, with input from AOS, NNSJ, and LHAC. CHRC, AOS, NNSJ, LHAC, and JRS performed the experiments, analyzed the data, and drafted the parts of the paper. CHRC, LCA, and MJAR wrote the final manuscript and revised statistical analyses. All authors read and approved the final version of the manuscript.

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Correspondence to Carlos Henrique Rocha Catalão.

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The authors declare no conflict of interest.

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The study procedures were performed according to the National Council of Animal Experiment Control (CONCEA) and with approval by the Institutional Animal Care and Use Committee at the School of Dentistry of Ribeirão Preto, University of São Paulo (Protocol Number #2019.1.51.58.6).

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Catalão, C.H.R., de Oliveira Souza, A., Santos-Junior, N.N. et al. Pre-treatment and continuous administration of simvastatin during sepsis improve metabolic parameters and prevent CNS injuries in survivor rats. Mol Cell Biochem 477, 2657–2667 (2022). https://doi.org/10.1007/s11010-022-04463-8

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