| Summary: | Xiaoshuai Ren,1,* Feng Lin,2,* Chaogang Tang,2,* Yao Liu,3 Guolei Liao,2 Jiabi Liang,3 Wenji Luo,3 Lei Zhang,2 Wenli Chen3 1Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, 519000, People’s Republic of China; 2Department of Cerebrovascular Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, 519000, People’s Republic of China; 3Department of Pharmacy, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, 519000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenli Chen; Lei Zhang, Tel +15626471884 ; +13726209240, Email chenwenl@mail3.sysu.edu.cn; zhangl92@mail.sysu.edu.cnPurpose: Stroke is a leading cause of disability and death globally. However, there are few clinical drugs for stroke therapy. Novel and effective neuroprotectants are called on the way.Methods: In this study, 93 steroids from a constructed steroidal library were randomly numbered and blindly evaluated in an L-glutamate-induced HT-22 oxidative stress model. The neuroprotective effects of 5 candidates were further investigated in potassium deprivation-induced apoptosis of cerebellar granule neurons (CGNs), D-glutamate-induced excitotoxicity of CGNs, and cortical neuron (CN) models.Results: Interestingly, unblinding revealed that cholest-4-ene-3,6-dione (78), a cholesterol derivative, was first found to have comprehensive neuroprotective effects in all cell models. 78 administration also decreased the infarction volume and improved motor function in middle cerebral artery occlusion (MCAO) model rats. Additionally, 78 treatment decreased intercellular reactive oxygen species (ROS) and NO production in the HT-22 cell model. Finally, lipidomics and molecular docking results showed that 78 may exert its neuroprotective effects by increasing platelet-activating factor (PAF) analog 1-(9Z-pentadecenoyl)-glycero-3-phosphocholine production.Conclusion: This study indicates that 78, a novel neuroprotectant, is a promising therapeutic candidate with comprehensive neuroprotective effects for the treatment of ischemic stroke by decreasing ROS/reactive nitrogen species (RNS) levels and increasing 1-(9Z-pentadecenoyl)-glycero-3-phospho-choline production. Keywords: neuroprotection, cholest-4-ene-3,6-dione, anti-ROS, lipidomics, molecular docking
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