Novel contact-kinin inhibitor sylvestin targets thromboinflammation and ameliorates ischemic stroke.

Abstract

Ischemic stroke is a leading cause of death and disability worldwide. Increasing evidence indicates that ischemic stroke is a thromboinflammatory disease in which the contact-kinin pathway has a central role by activating pro-coagulant and pro-inflammatory processes. The blocking of distinct members of the contact-kinin pathway is a promising strategy to control ischemic stroke. Here, a plasma kallikrein and active FXII (FXIIa) inhibitor (sylvestin, contained 43 amino acids, with a molecular weight of 4790.4 Da) was first identified from forest leeches (Haemadipsa sylvestris). Testing revealed that sylvestin prolonged activated partial thromboplastin time without affecting prothrombin time. Thromboelastography and clot retraction assays further showed that it extended clotting time in whole blood and inhibited clot retraction in platelet-rich plasma. In addition, sylvestin prevented thrombosis in vivo in FeCl3-induced arterial and carrageenan-induced tail thrombosis models. The potential role of sylvestin in ischemic stroke was evaluated by transient and permanent middle cerebral artery occlusion models. Sylvestin administration profoundly protected mice from ischemic stroke by counteracting intracerebral thrombosis and inflammation. Importantly, sylvestin showed no signs of bleeding tendency. The present study identifies sylvestin is a promising contact-kinin pathway inhibitor that can proffer profound protection from ischemic stroke without increased risk of bleeding.

• Authors: Zhiye Zhang, Chuanbin Shen, Mingqian Fang, Yajun Han, Chengbo Long, Weihui Liu, Min Yang, Ming Liu, Dengdeng Zhang, Qiqi Cao, Xue Chen, Yaqun Fang, Qiumin Lu, Zongliu Hou, Yaxiong Li, Zhenze Liu, Xi Lei, Heyu Ni, Ren Lai
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 79 Issue 5 Pg. 240 (Apr 13 2022) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 35416530 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Chemical References

• Kinins

Topics

• Animals
• Inflammation (drug therapy, prevention & control)
• Ischemic Stroke
• Kinins
• Mice
• Stroke (drug therapy)
• Thromboinflammation
• Thrombosis (drug therapy)