Polymyxin B Reduces Brain Injury in Ischemic Stroke Rat Through a Mechanism Involving Targeting ESCRT-III Machinery and RIPK1/RIPK3/MLKL Pathway

Endosomal sorting complex required for transport III (ESCRT-III) machinery is a key component to counteract the mixed lineage kinase domain-like pseudokinase (MLKL)-induced plasma membrane broken in cells undergoing necroptosis. Based on the bioinformatics analysis, polymyxin B, a polypeptide antibi...

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Bibliographic Details
Published in:Journal of cardiovascular translational research 2022-10, Vol.15 (5), p.1129-1142
Main Authors: Tian, Jing, Zhang, Yi-Yue, Peng, Ya-Wei, Liu, Bin, Zhang, Xiao-Jie, Hu, Zhong-Yang, Hu, Chang-Ping, Luo, Xiu-Ju, Peng, Jun
Format: Article
Language:English
Subjects:
Animals
Biomedical Engineering and Bioengineering
Biomedicine
Brain Injuries
Cardiology
Endosomal Sorting Complexes Required for Transport
Human Genetics
Ischemic Stroke
Medicine
Medicine & Public Health
Original Article
Polymyxin B
Protein Kinases - metabolism
Rats
Stroke
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Summary:Endosomal sorting complex required for transport III (ESCRT-III) machinery is a key component to counteract the mixed lineage kinase domain-like pseudokinase (MLKL)-induced plasma membrane broken in cells undergoing necroptosis. Based on the bioinformatics analysis, polymyxin B, a polypeptide antibiotic, is predicted to simultaneously interact with ESCRT-III subunits and necroptosis-relevant proteins. This study aims to explore whether polymyxin B could reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and/or suppressing the RIPK1/RIPK3/MLKL pathway. The stroke rats showed evident brain injury, concomitant with the downregulation of ESCRT-III subunits and the upregulation of necroptosis-relevant proteins. Post-ischemic administration of polymyxin B could alleviate the brain injury, accompanied by restoration of the levels of ESCRT-III subunits and suppression of necroptosis-relevant proteins. And, polymyxin B exerted similar effects in hypoxia-treated HT22 cells. We conclude that polymyxin B can reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and suppressing the RIPK1/RIPK3/MLKL pathway simultaneously. Graphical abstract
ISSN:1937-5387
1937-5395
DOI:10.1007/s12265-022-10224-1