Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-κB Signaling
Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-κB Signaling
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DOI：
10.1007/s12264-020-00601-8
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发表时间：
2020-10-27
影响因子：
5.6
通讯作者：
Qu, Yan
中科院分区：
文献类型：
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作者：
Luo, Jianing;Wu, Xun;Qu, Yan
创伤性脑损伤（TBI）触发内源性凝血机制的激活，并释放大量凝血酶以通过凝血酶受体（也称为蛋白酶激活受体（PAR））抑制无法控制的出血。然而，凝血酶是继发性脑损伤最关键的因素之一。因此，PAR可能是治疗出血性脑损伤的有效靶点。由于PAR 1拮抗剂在临床实践中具有增加的出血风险，因此PAR 4阻断剂被认为是更有希望的治疗方法。本研究旨在探讨PAR 4在TBI小鼠脑组织中的表达模式，并探讨新型选择性可逆性PAR 4拮抗剂BMS-986120（BMS）对继发性脑损伤的影响及其可能机制。用BMS治疗保护小鼠免受TBI。mRNA-seq分析、Western blot和qRT-PCR体外验证表明，BMS显著抑制凝血酶诱导的星形胶质细胞炎症反应，提示Tab 2/ERK/NF-κ B信号通路在此过程中起关键作用。我们的研究结果提供了可靠的证据，表明阻断PAR 4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。
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-kappa B 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.