Abstract
Abstract in English, Chinese 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 43.97 μmol/L and 6.37 μmol/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, FeCl 3-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. 血栓形成和炎症是缺血性脑卒中的主要病因。由于血浆激肽释放酶（PK）和凝血因子XII（FXIIa）启动的接触-激肽通路与凝血和炎症级联反应具有双向作用，因此，为缺血性脑卒中治疗药物的开发提供了方向。该研究发现蝙蝠（ Myotis myotis）源蛋白序列的寡肽 LE6（Leu-Ser-Glu-Glu-Pro-Glu，702 Da）能高效抑制PK 和 FXIIa 的活性，抑制常数分别为 43.97 μmol/L和 6.37 μmol/L。这是首次探究的PK和FXIIa双靶点活性抑制的寡肽与缺血性脑卒中治疗的关系。在体外，LE6 可延长血浆复钙和活化部分凝血活酶时间。在小鼠模型中，LE6能抑制卡拉胶诱导的小鼠尾部血栓形成、氯化铁诱导的颈动脉血栓形成和光化学诱导的脑内血栓形成。此外，LE6 还能明显减轻缺血性脑卒中小鼠模型中的炎症和脑缺血损伤。重要的是，LE6 的低毒性、低溶血性和低出血潜能，以及其合成的简易性，都凸显了其潜在的临床应用前景。该研究显示，蝙蝠源寡肽LE6作为FXIIa和PK的抑制剂，通过减少炎症和抑制血栓形成，对中风治疗有益。.