2. Academic Validation
  3. URB597 exerts neuroprotective effects against transient brain ischemia injury in mice by regulating autophagic flux and necroptosis

URB597 exerts neuroprotective effects against transient brain ischemia injury in mice by regulating autophagic flux and necroptosis

  • Eur J Pharmacol. 2023 Aug 10;175982. doi: 10.1016/j.ejphar.2023.175982.
Xiaoqian Yuan 1,  Wenxuan Ye 2,  Ling Chen 3,  Doudou Luo 4,  Li Zhou 5,  Yan Qiu 6,  Rengong Zhuo 3,  Yun Zhao 3,  Lu Peng 3,  Lichao Yang 3,  Xin Jin 2,  Yu Zhou 7
Affiliations

Affiliations

  • 1 Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Key Laboratory of Chiral Drugs, Xiamen, 361102, China. Electronic address: xiaoqiansapple@163.com.
  • 2 Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Key Laboratory of Chiral Drugs, Xiamen, 361102, China.
  • 3 Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China; Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Key Laboratory of Chiral Drugs, Xiamen, 361102, China.
  • 4 Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Key Laboratory of Chiral Drugs, Xiamen, 361102, China; State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, 361102, China.
  • 5 Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • 6 Key Laboratory of Chiral Drugs, Xiamen, 361102, China.
  • 7 Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China; Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, China; Key Laboratory of Chiral Drugs, Xiamen, 361102, China; State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, 361102, China. Electronic address: zhouyu@xmu.edu.cn.
PMID: 37572942 DOI: 10.1016/j.ejphar.2023.175982
Abstract

Ischemic stroke is a leading cause of death and disability, and medical treatments for ischemic stroke are very limited. URB597 is a potent and selective inhibitor of fatty acid amide hydrolase (FAAH). However, the effect of URB597 on ischemic stroke and the underlying molecular mechanisms remain little known. In this study, focal cerebral ischemia was induced by transient middle cerebral artery occlusion in mice. Our results showed that URB597 dose-dependently improved neurological function and reduced brain infarct volume and brain edema 24 h after brain ischemia. The most effective dose was 1 mg/kg and the therapeutic time window was within 3 h after ischemic stroke. To further investigate the underlying mechanism, Necroptosis and Autophagy flux were detected by Western blot and/or immunofluorescence staining with or without chloroquine, an autophagic flux inhibitor. Our results showed that URB597 promoted autophagic flux and reduced neuronal Necroptosis after brain ischemia and these effects could be abolished by chloroquine. In addition, we found that Peroxisome Proliferator-activated Receptor α (PPARα) antagonist GW6471 partly abolished the effect of URB597 against brain ischemia and URB597 upregulated the expressions of PPARα. In conclusion, URB597 exerts a neuroprotective effect in a dose- and time-dependent manner, and this effect may be related to its restoration of autophagic flux and inhibition of neuronal Necroptosis. PPARα is involved in the neuroprotective effect of URB597. This study provides novel evidence that URB597 may be a promising agent for the clinical treatment of ischemic stroke.

Keywords

Autophagy flux; Cerebral ischemia; Necroptosis; Peroxisome proliferator-activated receptor α; URB597.

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