Recombinant Netrin-1 binding UNC5B receptor attenuates neuroinflammation and brain injury via PPARγ/NFκB signaling pathway after subarachnoid hemorrhage in rats

被引：69

作者：

Xie, Zongyi ^{[1
,2
]}

Huang, Lei ^{[2
,3
,4
]}

Enkhjargal, Budbazar ^{[2
]}

Reis, Cesar ^{[2
]}

Wan, Weifeng ^{[2
]}

Tang, Jiping ^{[2
]}

Cheng, Yuan ^{[1
]}

Zhang, John H. ^{[2
,3
,4
]}

机构：

[1] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400010, Peoples R China

[2] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, 11041 Campus St,Risley Hall,Room 219, Loma Linda, CA 92354 USA

[3] Loma Linda Univ, Sch Med, Dept Anesthesiol, 11041 Campus St,Risley Hall,Room 219, Loma Linda, CA 92354 USA

[4] Loma Linda Univ, Sch Med, Dept Neurosurg, 11041 Campus St,Risley Hall,Room 219, Loma Linda, CA 92354 USA

来源：

BRAIN BEHAVIOR AND IMMUNITY | 2018年 / 69卷

基金：

美国国家卫生研究院;

关键词：

Brain edema; Early brain injury; Microglia; Netrin-1; Neuroinflammation; Subarachnoid hemorrhage; ISCHEMIA-REPERFUSION INJURY; INTRACEREBRAL HEMORRHAGE; INFLAMMATORY RESPONSE; CEREBRAL-ISCHEMIA; INNATE IMMUNITY; INHIBITION; ACTIVATION; KIDNEY; MACROPHAGES; ALPHA;

D O I：

10.1016/j.bbi.2017.11.012

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Neuroinflammation is an essential mechanism involved in the pathogenesis of subarachnoid hemorrhage (SAH)-induced brain injury. Recently, Netrin-1 (NTN-1) is well established to exert anti-inflammatory property in non-nervous system diseases through inhibiting infiltration of neutrophil. The present study was designed to investigate the effects of NTN-1 on neuroinflammation, and the potential mechanism in a rat model of SAH. Two hundred and ninety-four male Sprague Dawley rats (weight 280-330 g) were subjected to the endovascular perforation model of SAH. Recombinant human NTN-1 (rh-NTN-1) was administered intravenously. Small interfering RNA (siRNA) of NTN-1 and UNC5B, and a selective PPAR gamma antagonist bisphenol A diglycidyl ether (BADGE) were applied. Post-SAH evaluations included neurobehavioral function, brain water content, Western blot analysis, and immunohistochemistry. Our results showed that endogenous NTN-1 and its receptor UNC5B level were increased after SAH. Administration of rh-NTN-1 reduced brain edema, ameliorated neurological impairments, and suppressed microglia activation after SAH, which were concomitant with PPAR gamma activation, inhibition of NF kappa B, and decrease in TNF-alpha, IL-6, and ICAM-1, as well as myeloperoxidase (MPO). Knockdown of endogenous NTN-1 increased expression of pro-inflammatory mediators and MPO, and aggravated neuroinflammation and brain edema. Moreover, knockdown of UNC5B using specific siRNA and inhibition of PPAR gamma with BADGE blocked the protective effects of rh-NTN-1. In conclusion, our findings indicated that exogenous rh-NTN-1 treatment attenuated neuroinflammation and neurological impairments through inhibiting microglia activation after SAH in rats, which is possibly mediated by UNC5B/PPAR gamma/NF kappa B signaling pathway. Exogenous NTN-1 may be a novel therapeutic agent to ameliorating early brain injury via its anti-inflammation effect. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：190 / 202

页数：13

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