摘要
Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke.The contact-kinin pathway,initiated by plasma kallikrein(PK)and activated factor XII(FXIIa),functions bidirectionally with the coagulation and inflammation cascades,providing a novel target for therapeutic drug development in ischemic stroke.In this study,we identified a bat-derived oligopeptide from Myotis myotis(Borkhausen,1797),designated LE6(Leu-Ser-Glu-Glu-Pro-Glu,702 Da),with considerable potential in stroke therapy due to its effects on the contact kinin pathway.Notably,LE6 demonstrated significant inhibitory effects on PK and FXIIa,with inhibition constants of 43.97μmol/L and 6.37μmol/L,respectively.In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time.In murine models,LE6 effectively inhibited carrageenan-induced mouse tail thrombosis,FeCl3-induced carotid artery thrombosis,and photochemically induced intracerebral thrombosis.Furthermore,LE6 significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models.Notably,the low toxicity,hemolytic activity,and bleeding risk of LE6,along with its synthetic simplicity,underscore its clinical applicability.In conclusion,as an inhibitor of FXIIa and PK,LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation.
基金
supported by the National Natural Science Foundation of China(32200397,23SWAQ09,and 31930015)
Yunnan Province Grant(202302AA310032,202302AA310035,and 202003AD150008)
Ministry of Science and Technology of China(2018YFA0801403)
Chinese Academy of Sciences(SAJC202103 and KFJ-BRP-008-003)
New Cornerstone Investigator Program(NCI202238)
Kunming Science and Technology Bureau(2022SCP007)
Priority Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University(202101AC070461)
Basic Research Program of Yunnan Province Science and Technology Department(202301AT070083)。
