Diosmetin alleviates cerebral ischemia‐reperfusion injury through Keap1‐mediated Nrf2/ARE signaling pathway activation and NLRP3 inflammasome inhibition. Issue 6 (22nd February 2022)

• Record Type: Journal Article
• Authors: Shi, Min; Wang, Jianqiang; Bi, Fangfang; Bai, Zhangyong
• Is Part Of: Environmental toxicology. Volume 37:Issue 6(2022)
• Page Start: 1529
• Page End: 1542
• Publication Date: 2022-02-22
• Subjects: cerebral ischemia‐reperfusion -- diosmetin -- Keap1 -- NLRP3 inflammasome -- Nrf2/ARE signaling pathway; Water quality bioassay -- Periodicals; Water -- Pollution -- Toxicology -- Periodicals; Microbiological assay -- Periodicals; Toxicity testing -- Periodicals; Environmental toxicology -- Periodicals; Environmental Pollution -- Periodicals; Environmental Pollutants -- Periodicals; Environmental Monitoring -- Periodicals; Écotoxicologie -- Périodiques; Pollution -- Périodiques; 615.902
• DOI: 10.1002/tox.23504
• Languages: English
• ISSNs: 1520-4081

Abstract

Abstract: Diosmetin was found to exert protective effect on renal and myocardial ischemia‐reperfusion (IR) injury. This study aimed to investigate the role of diosmetin in cerebral IR (CIR) injury. PC12 neurons were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) to establish CIR injury model in vitro and then incubated with diosmetin, and we found that diosmetin alleviated OGD/R‐induced viability inhibition, LDH release, apoptosis, and oxidative stress in PC12 cells. Then our results showed that diosmetin downregulated kelch like ECH‐associated protein 1 (Keap1) expression, and upregulated nuclear factor E2‐related factor 2 (Nrf2) expression, antioxidant response element (ARE) activity and the mRNA and protein expression of heme oxygenase 1 (HO‐1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Keap1 overexpression or Nrf2 silencing both attenuated the neuroprotective effect of diosmetin on PC12 cells. Moreover, diosmetin inhibited the levels of nucleotide‐binding oligomerization domain (NOD)‐like receptor (NLR) pyrin domain containing 3 (NLRP3) inflammasome pathway related proteins and inflammatory cytokines interleukin (IL)‐1β and IL‐18. Additionally, a middle cerebral artery occlusion (MCAO) rat model was established and diosmetin was injected for treatment. Diosmetin alleviated CIR‐induced neurological deficits, cerebral infarction, brain edema and histopathological damage, and neuronal apoptosis and oxidative stress in MCAO rats. In conclusion, diosmetin attenuated OGD/R‐induced PC12 cell viability inhibition, apoptosis, oxidative stress and inflammation through Keap1‐mediated Nrf2/ARE signaling activation and NLRP3 inflammasome inhibition, and alleviated CIR‐induced neurological injury in MCAO rat model. Our study may provide a novel therapeutic strategy for CIR injury.