Jianing Luo¹ • Xun Wu¹ • Haixiao Liu¹ • Wenxing Cui¹ • Wei Guo¹ • Kang Guo¹ • Hao Guo¹ • Kai Tao¹ • Fei Li¹ • Yingwu Shi¹ • Dayun Feng¹ • Hao Yan² • Guodong Gao¹ • Yan Qu¹

¹ Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710038, China

² Department of Operative Dentistry and Endodontics, School of Stomatology, The Fourth Military Medical University, Xi’an 710038, China

Abstract

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.

Keywords

Protease-activated receptors; BMS; Traumatic brain injury; Inflammation; Astrocyte; Tab2

[Springerlink][PMC Full Text]