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PAF Receptor Inhibition Attenuates Neuronal Pyroptosis in Cerebral Ischemia/Reperfusion Injury

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Abstract

Ischemic stroke is an inflammation-related disease, during which process activation of NLRP3 inflammasome and subsequent pyroptosis play crucial roles. Platelet-activating factor (PAF) is a potent phospholipid regulator of inflammation which exerts its effect via binding specific PAF receptor (PAFR). However, whether PAFR contributes to pyroptosis during ischemia/reperfusion (I/R) injury remains to be elucidated. To explore the underlying effect of PAFR on ischemic stroke from the perspective of pyroptosis, mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) injury and primary cultures of mice cerebral cortical neurons were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) injury to mimic I/R in vivo and in vitro, after which indexes associated with pyroptosis were analyzed. Intriguingly, our results indicated that inhibition of PAFR with its inhibitor XQ-1H or PAFR siRNA exerted a neuroprotective effect against I/R injury both in vivo and in vitro. Furthermore, inflammasome activation and pyroptosis after ischemic challenge were attenuated by XQ-1H or PAFR siRNA. Besides, the protection of XQ-1H was abolished by PAF stimulaiton to some extent. Moreover, XQ-1H or PAFR siRNA alleviated the neuronal pyroptosis induced by LPS and nigericin (an NLRP3 activator) in cortical neurons. Taken together, this study firstly demonstrates that PAFR is involved in neuronal pyroptosis after I/R injury, and XQ-1H, a specific PAFR inhibitor, has a promising prospect in attenuating I/R injury from the perspective of anti-pyroptosis.

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

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Acknowledgements

The authors acknowledge the technical support from Cellular and Molecular Biology Center of China Pharmaceutical University.

Funding

This work was supported by Natural Science Foundation of China (Program No. 82073845) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteenth Five-year Plan Period (No. 2019ZX09301-134 and No. 2016ZX09101031, respectively).

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  1. Bo Zhao and Yuxiang Fei contributed equally to this work.

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  1. State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Bo Zhao, Yuxiang Fei, Jianping Zhu, Qiyang Yin, Weirong Fang & Yunman Li

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Yunman Li and Weirong Fang conceived the whole work design; Bo Zhao and Yuxiang Fei performed the experiments and wrote the manuscript; Jianping Zhu and Qiyang Yin helped carry out the experiments. All authors read and approved the final manuscript.

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Correspondence to Weirong Fang or Yunman Li.

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Zhao, B., Fei, Y., Zhu, J. et al. PAF Receptor Inhibition Attenuates Neuronal Pyroptosis in Cerebral Ischemia/Reperfusion Injury. Mol Neurobiol 58, 6520–6539 (2021). https://doi.org/10.1007/s12035-021-02537-0

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