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

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.

• Authors: Bo Zhao, Yuxiang Fei, Jianping Zhu, Qiyang Yin, Weirong Fang, Yunman Li
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 58 Issue 12 Pg. 6520-6539 (Dec 2021) ISSN: 1559-1182 [Electronic] United States
• PMID: 34562185 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Ginkgolides
• Inflammasomes
• Lactones
• Neuroprotective Agents
• Platelet Membrane Glycoproteins
• Receptors, G-Protein-Coupled
• XQ-1H compound
• platelet activating factor receptor

Topics

• Animals
• Disease Models, Animal
• Ginkgolides (pharmacology)
• Inflammasomes (metabolism)
• Lactones (pharmacology)
• Male
• Mice
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology)
• Platelet Membrane Glycoproteins (antagonists & inhibitors, genetics, metabolism)
• Pyroptosis (drug effects)
• Receptors, G-Protein-Coupled (antagonists & inhibitors, genetics, metabolism)
• Reperfusion Injury (metabolism)