Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via
- PDF / 2,530,319 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 9 Downloads / 208 Views
www.neurosci.cn www.springer.com/12264
ORIGINAL ARTICLE
Antagonism of Protease-Activated Receptor 4 Protects Against Traumatic Brain Injury by Suppressing Neuroinflammation via Inhibition of Tab2/NF-jB Signaling 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
•
Received: 15 January 2020 / Accepted: 19 July 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
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-jB signaling pathway plays Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12264-020-00601-8) contains supplementary material, which is available to authorized users. Jianing Luo, Xun Wu and Haixiao Liu contributed equally to this work. & Guodong Gao [email protected] & Yan Qu [email protected] 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
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
Introduction Traumatic brain injury (TBI) is one of the leading causes of death in people under 45 years of age worldwide, with high morbidity and mortality [1]. Survivors often suffer multiple severe neurological dysfunctions [2]. And the incidence of TBI seems to be on the rise globally [3]. The damage caused by TBI is mainly composed of two parts, primary mechanical damage and secondary damage [4]. These two parts are very different but partially overlap. The primary injury occurs immediately after the trauma, that is, the devastating damage of the structural integrity of the brain caused by mechanical forces [5]. Primary mechani
Data Loading...
