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The Protective Effect of PK-11195 on Cognitive Impairment in Rats Survived of Polymicrobial Sepsis

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Abstract

Sepsis is an organ dysfunction caused by a host’s unregulated response to infection, causing long-term brain dysfunction with microglial activation, the release of inflammatory components, and mitochondrial changes. Neuroinflammation can increase the expression of the 18-kD translocator protein (TSPO) in the mitochondria, leading to the activation of the microglia and the release of inflammatory components. The antagonist PK-11195 can modulate TSPO and reduce microglial activation and cognitive damage presented in an animal model of sepsis. The aim of this was to evaluate the effects of PK-11195 on long-term brain inflammation and cognitive impairment in an animal model of sepsis. Wistar rats, 60 days old, were submitted to cecal ligation and puncture (CLP) surgery, divided into groups control/saline, control/PK-11195, sepsis/saline, and sepsis/PK-11195. Immediately after surgery, the antagonist PK-11195 was administered at a dose of 3 mg/kg. Ten days after CLP surgery, the animals were submitted to behavioral tests and determination of brain inflammatory parameters. The sepsis/saline group presented cognitive damage. However, there was damage prevention in animals that received PK-11195. Besides, the sepsis increased the levels of cytokines and M1 microglia markers and caused oxidative damage. However, PK-11195 had the potential to decrease inflammation. These events show that the modulation of neuroinflammation during sepsis by PK-11195, possibly related to changes in TSPO, improves mitochondrial function in the animals’ brains. In conclusion, the antagonist PK-11195 attenuated brain inflammation and prevented cognitive impairment in animals subjected to sepsis.

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Data Availability

All the data generated and analyzed during this study are available from the corresponding author upon reasonable request.

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Funding

This research was supported by Universidade do Extremo Sul Catarinense (UNESC) and National Institute of Science and Technology—Translational Medicine (INCT).

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Authors and Affiliations

  1. Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, 88806-000, Brazil

    Diogo Dominguini, Amanda V. Steckert, Mariane R. Abatti, Jaqueline S. Generoso, Tatiana Barichello & Felipe Dal-Pizzol

  2. Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Tatiana Barichello

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  1. Diogo Dominguini
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Contributions

DD, FDF, and TB designed the study. DD and JSG prepared the manuscript. FDF and TB edited the manuscript and supervised the study. DD, AVS, MRA, and JSG were responsible behavioral tests and biochemical analysis. All the authors have approved the final version of the manuscript.

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Correspondence to Diogo Dominguini.

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All the experimental procedures were performed with the approval of the Ethics Committee from Universidade do Extremo Sul Catarinense (protocol number: 001/2015-1) and conformed to international regulations.

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Supplemental Fig 1

- Experimental design. 60 days after birth, the rats were subjected to sepsis and treated with PK 11195. After 10 days, open field behavioral tests, recognition of novel objects, and inhibitory avoidance were performed. Soon after, the prefrontal cortex and hippocampus brain tissues were extracted for the analysis of cytokines, oxidative damage, and markers of microglial activity. (PNG 4948 kb)

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Dominguini, D., Steckert, A.V., Abatti, M.R. et al. The Protective Effect of PK-11195 on Cognitive Impairment in Rats Survived of Polymicrobial Sepsis. Mol Neurobiol 58, 2724–2733 (2021). https://doi.org/10.1007/s12035-021-02294-0

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