Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation

Xun Li; Minghe Yao; Lingling Li; Huifen Ma; Yiran Sun; Xiangpeng Lu; Weipeng Jing; Shanshan Nie

doi:10.1016/j.phymed.2024.155578

Aloe-emodin alleviates cerebral ischemia-reperfusion injury by regulating microglial polarization and pyroptosis through inhibition of NLRP3 inflammasome activation

Phytomedicine. 2024 Apr 7:129:155578. doi: 10.1016/j.phymed.2024.155578. Online ahead of print.

Authors

Xun Li¹, Minghe Yao², Lingling Li², Huifen Ma³, Yiran Sun³, Xiangpeng Lu⁴, Weipeng Jing², Shanshan Nie⁴

Affiliations

¹ College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: lixunfit@hactcm.edu.cn.
² College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, PR China.
³ Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China.
⁴ The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, PR China.

PMID: 38621328
DOI: 10.1016/j.phymed.2024.155578

Abstract

Background: Microglial activation plays a crucial role in injury and repair after cerebral ischemia, and microglial pyroptosis exacerbates ischemic injury. NOD-like receptor protein 3 (NLRP3) inflammasome activation has an important role in microglial polarization and pyroptosis. Aloe-emodin (AE) is a natural anthraquinone compound originated from rhubarb and aloe. It exerts antioxidative and anti-apoptotic effects during cerebral ischemia/reperfusion (I/R) injury. However, whether AE affects microglial polarization, pyroptosis, and NLRP3 inflammasome activation remains unknown.

Purpose: This study aimed to explore the effects of AE on microglial polarization, pyroptosis, and NLRP3 inflammasome activation in the cerebral infarction area after I/R.

Methods: The transient middle cerebral artery occlusion (tMCAO) and oxygen-glucose deprivation/re-oxygenation (OGD/R) methods were used to create cerebral I/R models in vivo and in vitro, respectively. Neurological scores and triphenyl tetrazolium chloride and Nissl staining were used to assess the neuroprotective effects of AE. Immunofluorescence staining, quantitative polymerase chain reaction and western blot were applied to detect NLRP3 inflammasome activation and microglial polarization and pyroptosis levels after tMCAO or OGD/R. Cell viability and levels of interleukin (IL)-18 and IL-1β were measured. Finally, MCC950 (an NLRP3-specific inhibitor) was used to evaluate whether AE affected microglial polarization and pyroptosis by regulating the activation of the NLRP3 inflammasome.

Results: AE improved neurological function scores and reduced the infarct area, brain edema rate, and Nissl-positive cell rate following I/R injury. It also showed a protective effect on BV-2 cells after OGD/R. AE inhibited microglial pyroptosis and induced M1 to M2 phenotype transformation and suppressed microglial NLRP3 inflammasome activation after tMCAO or OGD/R. The combined administration of AE and MCC950 had a synergistic effect on the inhibition of tMCAO- or OGD/R-induced NLRP3 inflammasome activation, which subsequently suppressed microglial pyroptosis and induced microglial phenotype transformation.

Conclusion: AE exerts neuroprotective effects by regulating microglial polarization and pyroptosis through the inhibition of NLRP3 inflammasome activation after tMCAO or OGD/R. These findings provide new evidence of the molecular mechanisms underlying the neuroprotective effects of AE and may support the exploration of novel therapeutic strategies for cerebral ischemia.

Keywords: Aloe-emodin; Cerebral ischemia/reperfusion; Microglial polarization; Microglial pyroptosis; NLRP3 inflammasome activation.