Cell permeable HMGB1-binding heptamer peptide ameliorates neurovascular complications associated with thrombolytic therapy in rats with transient ischemic stroke

Journal of Neuroinflammation

卷:15

Miaoqin Tan¹  Miaodan Li¹  Yafang Hu¹  Chen Wang¹  Yong Gu¹  Xue Shi¹  Shumin Chen¹  Xiaoxi Liu¹  Yongfang Zhang¹  Liang Zhou¹  Chenfei Lyu¹  Nailiang Zang¹  Jiangang Shen² 

[1] Department of Neurology, Nanfang Hospital, Southern Medical University;

[2] School of Chinese Medicine, The University of Hong Kong;

关键词: Ischemic stroke;    Tissue-type plasminogen activator;    Blood–brain barrier;    Hemorrhagic transformation;    HMGB1;    HMGB1-binding heptamer peptide;   

DOI  :  10.1186/s12974-018-1267-5

来源: DOAJ

【 摘 要 】

Abstract Background Blood–brain barrier (BBB) breakdown and inflammatory responses are the major causes of tissue-type plasminogen activator (tPA)-induced hemorrhagic transformation (HT), while high-mobility group box 1 (HMGB1) exacerbates inflammatory damage to BBB during the process of brain ischemia/reperfusion. This study aimed to investigate the change of HMGB1 after thrombolytic therapy and whether blocking HMGB1 could ameliorate the neurovasculature complications secondary to tPA treatment in stroke rats. Methods Sera from acute stroke patients and rats with thrombolytic therapy were collected to investigate HMGB1 secretion. Male Sprague-Dawley rats with 2 h or 4.5 h middle cerebral artery occlusion were continuously infused with tPA followed by administration of membrane permeable HMGB1-binding heptamer peptide (HBHP). The mortality rate, neurological score, HT, brain swelling, BBB permeability, and inflammatory factors were determined. Results The results revealed that HMGB1 levels were elevated in both stroke patients and rats after tPA treatment. Blocking HMGB1 signaling by HBHP in the rat model of 4.5 h brain ischemia significantly attenuated tPA-related complications, including mortality rate, the degree of hemorrhage, brain swelling, neurological deficits, BBB impairment, microglia activation, and the expressions of inflammatory cytokines. Conclusions tPA treatment might induce HMGB1 secretion while blocking HMGB1 with HBHP could markedly reduce the risk of thrombolysis-associated brain hemorrhage and mortality through attenuating BBB damage and inflammatory reactions. These results indicate that HMGB1 may potentiate the risk of HT in tPA administration and that blocking HMGB1 signaling would be helpful in preventing complications brought by thrombolysis in ischemic stroke. Trial registration http://www.chictr.org.cn. Unique identifier: ChiCTR-OOC-16010052. Registered 30 November 2016.

【 授权许可】

Unknown