2. Academic Validation
  3. Seratrodast, a thromboxane A2 receptor antagonist, inhibits neuronal ferroptosis by promoting GPX4 expression and suppressing JNK phosphorylation

Seratrodast, a thromboxane A2 receptor antagonist, inhibits neuronal ferroptosis by promoting GPX4 expression and suppressing JNK phosphorylation

  • Brain Res. 2022 Nov 15:1795:148073. doi: 10.1016/j.brainres.2022.148073.
Ying Hao 1,  Yitao Ou 2,  Cheng Zhang 2,  Hao Chen 2,  Hu Yue 2,  Zhongjin Yang 2,  Xiaofen Zhong 3,  Wenhui Hu 4,  Ping Sun 5
Affiliations

Affiliations

  • 1 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China; Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.
  • 3 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: huwenhui@gzhmu.edu.cn.
  • 5 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China. Electronic address: josp124@foxmail.com.
PMID: 36075466 DOI: 10.1016/j.brainres.2022.148073
Abstract

More than 30 % of individuals with epilepsy are refractory to currently available drugs, highlighting the urgent need to develop novel candidate drugs. Accumulating evidence implicates the key role of Ferroptosis in the pathophysiology of epileptic seizuresand its potential as a new drug target. Drug repurposing is a promising strategy for the rapid generation of new candidate drugs from the market drugs with new therapeutic indications, such as the best-selling drug thalidomide. Herein, we reported the discovery of Seratrodast, a market drug of thromboxane A2 receptor antagonist as a new Ferroptosis inhibitor (IC50: 4.5 μmol·L-1). Seratrodast could reduce lipid ROS production, regulate the system xc-/glutathione (GSH)/Glutathione Peroxidase 4 (GPX4) axis, and inhibit JNK phosphorylation and p53 expression. In addition, Seratrodast elevated GPX4 expression and decreased JNK phosphorylation in pentylenetetrazole-induced seizures in mice. Seratrodast increased the latency of seizures and reduced seizure duration in pentylenetetrazole-induced seizures. Our results suggest Seratrodast might be either a Ferroptosis inhibitor or a novel lead compound for further optimization of novel drug discovery.

Keywords

Ferroptosis; GPX4; Lipid peroxidation; Seizure; Seratrodast.

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