Pretreatment of Indobufen and Aspirin and their Combinations with Clopidogrel or Ticagrelor Alleviates Inflammasome Mediated Pyroptosis Via Inhibiting NF-κB/NLRP3 Pathway in Ischemic Stroke

Abstract

Increasing studies showed that several anti-platelet drugs turned out to be a promising strategy for inflammatory response. In this study, we investigated the protective efficiency of pretreatment of indobufen or aspirin combined with clopidogrel or ticagrelor (IACT) on cerebral ischemic injury via NF-κB/NLRP3 pathway. Ischemia/reperfusion (I/R) injury was simulated in vivo by middle cerebral artery occlusion/reperfusion (MCAO/R) model, and rats were pretreated with indobufen and aspirin and their combinations with clopidogrel or ticagrelor respectively. The platelet aggregation, cerebral infarct size, water content, neurological impairment and LDH release were measured. The relative expression of inflammasome mediated pyroptosis was determined by ELISA, RT-PCR, Tunel, Immunofluorescence and Western blotting as appropriate. In vitro, I/R injury was simulated in PC12 cells using oxygen glucose deprivation/reperfusion (OGD/R) and Lipopolysaccharide (LPS) to induce pyroptosis. The effect of combinations were significantly greater than MCAO/R group on decreasing the platelet aggregation, infarct size, brain edema, LDH release and neurologic impairment. LPS aggravated I/R-induced PC12 cell injury, which was significantly suppressed by pretreatment of IACT and Bay11–7082. Mechanistically, IACT alleviated transcriptionally encoded IL-1β, IL-18 and NLRP3 via inhibiting nuclear transportation of NF-κB. Importantly, at protein level, NLRP3, Caspase-1, IL-18, IL-1β and GSDMD were significantly decreased in combination groups both in vivo and vitro. IACT reduce inflammasome mediated pyroptosis in MCAO/R rats and OGD/R PC12 cells through inhibiting NF-κB/NLRP3 signaling pathway, which suggests that drug combination is a protective strategy with clinical potential against I/R-induced injury.

Graphical abstract

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Acknowledgements

This project was supported by National Science and Technology Major Project of the Ministry of Science and Technology of China [2016ZX09101031] and [2018ZX09301043] and China Pharmaceutical University “Double First-Class” Construction Technology Innovation Team Project [CPU2018GY23] and [CPU2018GY24].

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F.L. and D.X. performed most of the experiments and were involved in writing a draft manuscript; K.H., X.G. and N.L. performed information consolidation and were involved in modifying article; Y.L and W.F. were involved in selecting theme. All authors read and approved the final manuscript.

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Correspondence to Weirong Fang or Yunman Li.

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Li, F., Xu, D., Hou, K. et al. Pretreatment of Indobufen and Aspirin and their Combinations with Clopidogrel or Ticagrelor Alleviates Inflammasome Mediated Pyroptosis Via Inhibiting NF-κB/NLRP3 Pathway in Ischemic Stroke. J Neuroimmune Pharmacol (2021). https://doi.org/10.1007/s11481-020-09978-9

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Keywords

  • Ischemic stroke
  • Ischemia/reperfusion injury
  • Pyroptosis
  • Drug combinations
  • Inflammatory
  • NF-κB/NLRP3 pathway