Traumatic brain injury (TBI) triggers the activation of the endogenous coagulation mechanism, and a large amount of thrombin is released to curb uncontrollable bleeding through thrombin receptors, also known as protease-activated receptors (PARs). However, thrombin is one of the most critical factors in secondary brain injury. Thus, the PARs may be effective targets against hemorrhagic brain injury. Since the PAR1 antagonist has an increased bleeding risk in clinical practice, PAR4 blockade has been suggested as a more promising treatment. Here, we explored the expression pattern of PAR4 in the brain of mice after TBI, and explored the effect and possible mechanism of BMS-986120 (BMS), a novel selective and reversible PAR4 antagonist on secondary brain injury. Treatment with BMS protected against TBI in mice. mRNA-seq analysis, Western blot, and qRT-PCR verification in vitro showed that BMS significantly inhibited thrombin-induced inflammation in astrocytes, and suggested that the Tab2/ERK/NF-κB signaling pathway plays a key role in this process. Our findings provide reliable evidence that blocking PAR4 is a safe and effective intervention for TBI, and suggest that BMS has a potential clinical application in the management of TBI.

创伤性脑损伤 (TBI) 触发内源性凝血机制的激活，并通过凝血酶受体（也称为蛋白酶激活受体 (PAR)）释放大量凝血酶来抑制无法控制的出血。然而，凝血酶是继发性脑损伤的最关键因素之一。因此，PAR可能是对抗出血性脑损伤的有效靶点。由于 PAR1 拮抗剂在临床实践中具有增加的出血风险，因此 PAR4 阻断剂被认为是一种更有希望的治疗方法。在这里，我们探索了 TBI 后小鼠大脑中 PAR4 的表达模式，并探讨了 BMS-986120 (BMS) 这种新型选择性和可逆 PAR4 拮抗剂对继发性脑损伤的作用和可能的机制。用 BMS 治疗可保护小鼠免受 TBI。mRNA-seq 分析，Western 印迹，体外研究表明，BMS 显着抑制凝血酶诱导的星形胶质细胞炎症，提示 Tab2/ERK/NF-κB 信号通路在这一过程中起关键作用。我们的研究结果提供了可靠的证据，表明阻断 PAR4 是一种安全有效的 TBI 干预措施，并表明 BMS 在 TBI 管理中具有潜在的临床应用。