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

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.

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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

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).

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Correspondence to Qiang Wang.

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

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Zhang, Z., Lei, Y., Yan, C. et al. Probenecid Relieves Cerebral Dysfunction of Sepsis by Inhibiting Pannexin 1-Dependent ATP Release. Inflammation 42, 1082–1092 (2019). https://doi.org/10.1007/s10753-019-00969-4

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KEY WORDS

  • probenecid
  • pannexin 1
  • cecal ligation and puncture
  • neuroinflammation
  • cognitive impairment