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Matrix Metalloproteinase-2 and Metalloproteinase-9 Activities are Associated with Blood–Brain Barrier Dysfunction in an Animal Model of Severe Sepsis

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Abstract

There is no description on the mechanisms associated with blood–brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.

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Acknowledgments

This work was funded by NENASC project (PRONEX program CNPq/FAPESC); INCT-TM; PROCAD Sepse—CAPES.

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None.

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Authors and Affiliations

  1. Laboratório de Fisiopatologia Experimental and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil

    Felipe Dal-Pizzol, Hugo Alberto Rojas, Emilia Marcelina dos Santos, Francieli Vuolo, Larissa Constantino, Fabrícia Petronilho & Cristiane Ritter

  2. Laboratório de Neurociências and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil

    Gustavo Feier, Clarissa M. Comim & João Quevedo

  3. Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Matheus Pasquali, Daniel Pens Gelain & José Cláudio Fonseca Moreira

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  1. Felipe Dal-Pizzol
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  2. Hugo Alberto Rojas
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  3. Emilia Marcelina dos Santos
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  6. Gustavo Feier
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  7. Matheus Pasquali
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  8. Clarissa M. Comim
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  11. João Quevedo
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  12. José Cláudio Fonseca Moreira
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  13. Cristiane Ritter
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Corresponding author

Correspondence to Felipe Dal-Pizzol.

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Authors’ contribution

HRA, EMS, FP, FD-P, and CR were involved in the conception, hypotheses delineation, and design of the study. FV, RAM, LC, GF, MP, and CMC performed the acquisition of the data or analyzed such information. HRA, DPG, JCFM, CR, JQ, and FD-P wrote the article or were substantially involved in its revision prior to submission.

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Dal-Pizzol, F., Rojas, H.A., dos Santos, E.M. et al. Matrix Metalloproteinase-2 and Metalloproteinase-9 Activities are Associated with Blood–Brain Barrier Dysfunction in an Animal Model of Severe Sepsis. Mol Neurobiol 48, 62–70 (2013). https://doi.org/10.1007/s12035-013-8433-7

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  • DOI: https://doi.org/10.1007/s12035-013-8433-7

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