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Inflammation

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Probenecid Relieves Cerebral Dysfunction of Sepsis by Inhibiting Pannexin 1-Dependent ATP Release

  • Zhanqin Zhang
  • Yi Lei
  • Chaoying Yan
  • Xiaopeng Mei
  • Tao Jiang
  • Zhi Ma
  • Qiang WangEmail author
ORIGINAL ARTICLE
  • 16 Downloads

Abstract

Acute brain dysfunction and the following neurological manifestation are common complications in septic patients, which are associated with increased morbidity and mortality. However, the therapeutic strategy of this disorder remains a major challenge. Given the emerging role of a clinically approved drug, probenecid (PRB) has been recently identified as an inhibitor of pannexin 1 (PANX1) channel, which restrains extracellular ATP release-induced purinergic pathway activation and inflammatory response contributing to diverse pathological processes. In this study, we explored whether PRB administration attenuated neuroinflammatory response and cognitive impairment during sepsis. In mice suffered from cecal ligation and puncture (CLP)-induced sepsis, treatment with PRB improved memory retention and lessened behavioral deficits. This neuroprotective effect was coupled with restricted overproduction of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and interleukin (IL)-1β in the hippocampus. Since this damped neuroinflammation was replicated by inhibition of ATP release, it suggested that PANX1 channel modulates a purinergic-related pathway contributing to the neurohistological damage. Therefore, we identified PRB could be a promising therapeutic approach for the therapy of cerebral dysfunction of sepsis.

KEY WORDS

probenecid pannexin 1 cecal ligation and puncture neuroinflammation cognitive impairment 

Notes

Acknowledgements

The authors thank the National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine and Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research for providing the platform of some biochemistry experiments, and Dr. Hao Hu for providing guidance and standards of the behavioral experiments.

Funding Information

This work was supported by the Overseas, Hong Kong & Macao Scholars Collaborated Researching Fund (Grant No. 81529004) and the National Natural Science Foundation of China (Grant Nos. 81774113 and 81801958).

Compliance with Ethical Standards

All animal experiments were approved by the Institutional Animal Care and Use Committees of Xi’an Jiaotong University (Xi’an, China).

Competing Interests

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Zhanqin Zhang
    • 1
  • Yi Lei
    • 2
  • Chaoying Yan
    • 1
  • Xiaopeng Mei
    • 1
  • Tao Jiang
    • 1
  • Zhi Ma
    • 1
  • Qiang Wang
    • 1
    Email author
  1. 1.Department of Anesthesiology, Center for Brain ScienceThe First Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  2. 2.Department of AnesthesiologyGeneral Hospital of Xinjiang Military RegionXinjiangChina

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