TAK-242, an antagonist for Toll-like receptor 4, protects against acute cerebral ischemia/reperfusion injury in mice

• Type of Material: Article
• Authors: Fang Hua, Emory University; Huiling Tang, Emory University; Jun Wang, Emory University; Megan C. Prunty, Emory University; Xiaodong Hua, University of Georgia; Iqbal Sayeed, Emory University; Donald Stein, Emory University
• Language: English
• Date: 2015-04-01
• Publisher: SAGE Publications (UK and US)
• Publication Version: Final Published Version
• Copyright Statement: © 2015 International Society for Cerebral Blood Flow & Metabolism, Inc.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1038/jcbfm.2014.240
• Title of Journal or Parent Work: Journal of Cerebral Blood Flow and Metabolism
• ISSN: 0271-678X
• Volume: 35
• Issue: 4
• Start Page: 536
• End Page: 542
• Grant/Funding Information: This work was supported by AHA National Program SDG 0830481N, National Natural Science Foundation of China (30970995; 81271268), Jiangsu Specially Appointed Professor Program, and Jiangsu Six Major Talent Summit Programs to FH, and partly by NIH 5R01NS048451 and 1R01HD061971 to DGS.
• Keywords: neuroprotection; EXPRESSION; Life Sciences & Biomedicine; ACUTE ISCHEMIC-STROKE; PATHWAY; cerebral ischemia/reperfusion; NEURODEGENERATION; Toll-like receptors; TAK-242; Neurosciences & Neurology; Neurosciences; Science & Technology; SIGNAL-TRANSDUCTION INHIBITOR; Endocrinology & Metabolism; BRAIN-BARRIER PERMEABILITY; Hematology; RATS; TLR4; CHEMOKINE; TOLL-LIKE-RECEPTOR-4
• Research Categories: Biology, Neuroscience

Abstract

Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.