1. Academic Validation
  2. Cepharanthine attenuates cerebral ischemia/reperfusion injury by reducing NLRP3 inflammasome-induced inflammation and oxidative stress via inhibiting 12/15-LOX signaling

Cepharanthine attenuates cerebral ischemia/reperfusion injury by reducing NLRP3 inflammasome-induced inflammation and oxidative stress via inhibiting 12/15-LOX signaling

  • Biomed Pharmacother. 2020 Jul;127:110151. doi: 10.1016/j.biopha.2020.110151.
Jie Zhao 1 Xiangyu Piao 1 Yue Wu 2 Shanshan Liang 3 Fang Han 4 Qian Liang 1 Shujuan Shao 5 Dewei Zhao 6
Affiliations

Affiliations

  • 1 Department of Neurology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China.
  • 2 Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China.
  • 3 Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China.
  • 4 Department of Radiology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China.
  • 5 Key Laboratory of Proteomics, Dalian Medical University, Dalian 116044, People's Republic of China. Electronic address: shaoshujuan_2017@163.com.
  • 6 Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, People's Republic of China. Electronic address: zhaodewei_2016@126.com.
Abstract

Cepharanthine (CEP) is a potential candidate for treatment of cerebral ischemia/reperfusion (I/R) injury, due to its anti-inflammatory and anti-oxidative properties. To investigate the effect of CEP on cerebral I/R injury, we established a mouse model of transient middle cerebral artery occlusion (tMCAO) and a microglia cell model of oxygen and glucose deprivation/reoxygenation (OGD/R). Administration of CEP attenuated neurological deficits, reduced infarct volume and edema, and decreased microglia activation in MCAO mice. Immunofluorescence staining showed an up-regulation in NLR Family Pyrin Domain Containing 3 (NLRP3) immunoreactivity in Iba1-labled microglia together with total Iba1 and NLRP3 expression in the brain following tMCAO, while down-regulated by CEP treatment. In both tMCAO-induced mice and OGD/R-treated BV-2 cells, CEP exhibited dose-dependent inhibition on the expression of NLRP3, ASC and cleaved Caspase-1. Importantly, CEP attenuated tMCAO or OGD/R-induced overproduction of M1 microglia-regulated pro-inflammation cytokines IL-1β and IL-18, suggesting that CEP might involve in suppressing microglia polarization to M1 phenotype in vivo and in vitro. Moreover, CEP dose-dependently inhibited tMCAO-induced arachidonate 15 Lipoxygenase (ALOX15) together with Iba1-labled microglia. The subsequent ALOX15-mediated oxidative stress was decreased by CEP treatment in vivo and in vitro, as evidenced by reduced ROS generation and MDA level, and increased SOD activity. Taken together, we demonstrate that CEP attenuates cerebral I/R injury probably by inhibiting microglia activation and NLRP3 inflammasome-induced inflammation and reducing oxidative stress via suppressing 12/15-LOX signaling.

Keywords

12/15-LOX; NLRP3-inflammasome; cepharanthine; ischemia/reperfusion; microglia; oxidative stress.

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