Bergapten attenuates microglia-mediated neuroinflammation and ischemic brain injury by targeting Kv1.3 and Carbonyl reductase 1.

Shenghan Gao, Xinxin Zou, Zibu Wang, Xin Shu, Xiang Cao, Shengnan Xia, Pengfei Shao, Xinyu Bao, Haiyan Yang, Yun Xu, Pinyi Liu

Journal: European journal of pharmacology 2022;933():175242

PMID: 36058290

Full Text on Elsevier Science View on PubMed

Abstract

Microglia-mediated neuroinflammation plays a vital role in the pathogenesis of ischemic stroke, which serves as a prime target for developing novel therapeutic agent. However, feasible and effective agents for controlling neuroinflammation are scarce. Bergapten were acknowledged to hold therapeutic potential in restricting inflammation in multiple diseases, including peripheral neuropathy, migraine headaches and osteoarthritis. Here, we aimed to investigate the impact of bergapten on microglia-mediated neuroinflammation and its therapeutic potential in ischemic stroke. Our study demonstrated that bergapten significantly reduced the expression of pro-inflammatory cytokines and the activation of NF-κB signaling pathway in LPS-stimulated primary microglia. Mechanistically, bergapten suppressed cellular potassium ion efflux by inhibiting Kv1.3 channel and inhibits the degradation of Carbonyl reductase 1 induced by LPS, which might contribute to the anti-inflammatory effect of bergapten. Furthermore, bergapten suppressed microglial activation and post-stroke neuroinflammation in an experimental stroke model, leading to reduced infarct size and improved functional recovery. Thus, our study identified that bergapten might be a potential therapeutic compound for the treatment of ischemic stroke.

Address: Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210008, China.; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China.; Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210008, China; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, 210008, China; Jiangsu Provincial Key Discipline of Neurology, Nanjing, 210008, China; Nanjing Neurology Medical Center, Nanjing, 210008, China. Electronic address: [email protected].; Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, 210008, China. Electronic address: [email protected].

DOI: 10.1016/j.ejphar.2022.175242

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MeSH Terms: 5-Methoxypsoralen, Anti-Inflammatory Agents, Brain Injuries, Carbonyl Reductase (NADPH), Cytokines, Humans, Ischemic Stroke, Kv1.3 Potassium Channel, Lipopolysaccharides, Microglia, NF-kappa B, Neuroinflammatory Diseases, Potassium