Abstract:

This study aims to explore the protective effect of a new glycyrrhetinic acid derivative (code: YCY-20) on acute cerebral ischemia-reperfusion injury (CIRI) in rats, and analyze it’s possible mechanism by network pharmacology and molecular docking. SD rats were randomly divided into sham operation group, middle cerebral artery occlusion/reperfusion (MCAO/R) group and YCY-20 treatment group; Zea-longa score and open field test were used for neurobehavioral test; TTC staining, HE staining and Nissl staining were used to observe the changes of cerebral infarction and pathological changes of neurons and nissl bodies; TUNEL staining was used to detect the level of neuronal apoptosis; The changes of plasma inflammatory factors were detected by ELISA. Then the targets of YCY-20 and ischemic stroke (IS) were screened through SwissTargetPrediction website, GeneCard, DisGeNET and other disease databases; Using Omicshare platform and STRING database to obtain intersection targets and prediction pathways, and using AutoDock Vina 1.5.7 software to conduct molecular docking between YCY-20 and core targets. The results of animal experiments show that, YCY-20 could reduce MCAO/R-induced neurological damage (P < 0.05), improving the autonomic motor function of rats, reduce cerebellar ischemic lesions (P < 0.01), reduce the pathological damage of neurons, inhibit the apoptosis of nerve cells (P < 0.01), and down regulate the expression levels of tumor necrosis factor-α (TNF-α) (P < 0.05), interleukin-6 (IL-6) (P < 0.01) and IL-1β (P < 0.05) in rat plasma. Network pharmacology predicted 37 core targets of YCY-20 for the treatment of IS, including signal transducer and activator of transcription 3 (STAT3), mitogen activated protein kinase 3 (MAPK3), and toll-like receptor 4 (TLR4); KEGG pathway analysis results suggest that the protective effect of YCY-20 on IS may be related to vascular endothelial growth factor (VEGF) signaling pathway, hypoxia inducible factor-1 (HIF-1) signaling pathway, advanced glycation endproducts (AGE)-the receptor of AGE (RAGE) in diabetic complications and other signaling pathways; Molecular docking results showed that YCY-20 had strong binding affinity with the above key targets. In conclusion, YCY-20 may alleviate acute CIRI in rats by inhibiting neuroinflammation and apoptosis through multiple targets and pathways.

Key words: cerebral ischemia-reperfusion injury, network pharmacology, molecular docking, novel glycyrrhetinic acid derivatives