Atorvastatin‐induced intracerebral hemorrhage is inhibited by berberine in zebrafish

• Published in: Journal of applied toxicology 2024-08, Vol.44 (8), p.1198-1213
• Main Authors: Liu, Xin‐Yan, Chen, Bo, Zhang, Rui, Zhang, Miao‐Qing, Ma, Yuan‐Yuan, Han, Ying, Jiang, Jian‐Dong, Zhang, Jing‐Pu
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Atorvastatin; Atorvastatin - pharmacology; autophagy; Berberine; Berberine - pharmacology; Brain; Brain injury; Cardiovascular diseases; Cell membranes; Cerebral Hemorrhage - chemically induced; Danio rerio; Disease Models, Animal; Endothelial cells; Endothelial Cells - drug effects; Hemocytes; Hemorrhage; Hyperlipidemia; Immunoprecipitation; Integrity; intracerebral hemorrhage; Lipids; Localization; Locomotion; occludin; Phosphorylation; Statins; Stroke; vascular integrity; VE‐cadherin; Zebrafish
• ISSN: 0260-437X; 1099-1263; 1099-1263
• DOI: 10.1002/jat.4614

Intracerebral hemorrhage (ICH), for which there are currently no effective preventive or treatment methods, has a very high fatality rate. Statins, such as atorvastatin (ATV), are the first‐line drugs for regulating blood lipids and treating hyperlipidemia‐related cardiovascular diseases. However, ATV‐associated ICH has been reported, although its incidence is rare. In this study, we aimed to investigate the protective action and mechanisms of berberine (BBR) against ATV‐induced brain hemorrhage. We established an ICH model in zebrafish induced by ATV (2 μM) and demonstrated the effects of BBR (10, 50, and 100 μM) on ICH via protecting the vascular network using hemocyte staining and three transgenic zebrafish. BBR was found to reduce brain inflammation and locomotion injury in ICH‐zebrafish. Mechanism research showed that ATV increased the levels of VE‐cadherin and occludin proteins but disturbed their localization at the cell membrane by abnormal phosphorylation, which decreased the number of intercellular junctions between vascular endothelial cells (VECs), disrupting the integrity of vascular walls. BBR reversed the effects of ATV by promoting autophagic degradation of phosphorylated VE‐cadherin and occludin in ATV‐induced VECs examined by co‐immunoprecipitation (co‐IP). These findings provide crucial insights into understanding the BBR mechanisms involved in the maintenance of vascular integrity and in mitigating adverse reactions to ATV. This study investigated the effect of berberine on atorvastatin‐induced cerebral hemorrhage in zebrafish. Our results indicate that BBR enhances the survival rate of zebrafish with brain hemorrhage, reduces hemorrhage and inflammation, and improves the locomotion function of ICH‐zebrafish by stabilizing vascular integrity. In vitro experiments using HUVEC cells show that BBR counteracts the adverse effects of ATV on endothelial cell connections by promoting the autophagic degradation of intracellularly phosphorylated connexins. These findings suggest the potential of BBR as a treatment for hemorrhagic stroke.