Blockade of high mobility group box-1 signaling via the receptor for advanced glycation end-products ameliorates inflammatory damage after acute intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) is a devastating disease with no specific treatment. Increasing evidence indicates that inflammatory response plays a critical role in ICH-induced damage. High mobility group box-1 protein (HMGB1) may trigger inflammatory response via three putative receptors: receptor for advanced glycation end-products (RAGE), toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4). Which receptor participates in HMGB1-induced inflammation during acute ICH is unknown. Using a rat model to examine the early phase of injury in collagenase-induced ICH, we found that treating animals with HMGB1 antagonist significantly reduced the expression of all three receptors. Treating animals with the HMGB1 antagonist EP or RAGE antagonist FPS-ZM1 significantly reduced inflammatory cell infiltration and expression of IL-1β, matrix metalloproteinase-9 in the perihematoma after ICH. Treatment with EP or FPS-ZM1 also led to greater neurobehavioral function and less brain edema, hemorrhage volume and brain damage after ICH. In contrast, treatment with TLR2/4 antagonists did not significantly affect these post-ICH outcomes. Our results suggest that RAGE may play a specific role in the acute phase of ICH, so targeting the HMGB1-RAGE signaling pathway may be a promising therapeutic strategy.
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China. Electronic address: lidan_2008@126.com.
Dan
D
Li
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China. Electronic address: leichunyan328@163.com.
Chunyan
C
Lei
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China. Electronic address: shutingzhangyang@gmail.com.
Shuting
S
Zhang
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China; State Key Laboratory of Human Disease Biotherapy, Ministry of Education, West China Hospital, Sichuan University, PR China. Electronic address: zsh9@hotmail.com.
Shihong
S
Zhang
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China; State Key Laboratory of Human Disease Biotherapy, Ministry of Education, West China Hospital, Sichuan University, PR China. Electronic address: wyplmh@hotmail.com.
Ming
M
Liu
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, PR China; State Key Laboratory of Human Disease Biotherapy, Ministry of Education, West China Hospital, Sichuan University, PR China. Electronic address: dragonwbtxf@hotmail.com.
Bo
B
Wu
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000378:metabolism* / Q000473:pathology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D001549:Benzamides; C572629:FPS-ZM1; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D053583:Interleukin-1beta; D011773:Pyruvates; D000067759:Receptor for Advanced Glycation End Products; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C046522:ethyl pyruvate; D020780:Matrix Metalloproteinase 9
High mobility group box-1; Inflammation; Intracerebral hemorrhage; Receptor for advanced glycation end-products