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Author Notes:

Correspondence: Dr F Hua, Department of Neurology, Affiliated Hospital of Xuzhou Medical College, 99 West Huaihai Road, Xuzhou, Jiangsu 221002, PR China. E-mail: huafang@xzmc.edu.cn

The authors declare no conflict of interest.

Subject:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Endocrinology & Metabolism
  • Hematology
  • Neurosciences
  • Neurosciences & Neurology
  • cerebral ischemia/reperfusion
  • neuroprotection
  • TAK-242
  • Toll-like receptors
  • ACUTE ISCHEMIC-STROKE
  • SIGNAL-TRANSDUCTION INHIBITOR
  • BRAIN-BARRIER PERMEABILITY
  • RATS
  • EXPRESSION
  • TLR4
  • TOLL-LIKE-RECEPTOR-4
  • NEURODEGENERATION
  • CHEMOKINE
  • PATHWAY

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

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Journal Title:

Journal of Cerebral Blood Flow and Metabolism

Volume:

Volume 35, Number 4

Publisher:

, Pages 536-542

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 International Society for Cerebral Blood Flow & Metabolism, Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (http://creativecommons.org/licenses/by-nc-sa/3.0/).

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