Early toll-like receptor 4 blockade reduces ROS and inflammation triggered by microglial pro-inflammatory phenotype in rodent and human brain ischaemia models

Esther Parada, Ana I. Casas, Alejandra Palomino-Antolin, Vanessa Gomez-Rangel, Alfonso Rubio-Navarro, Victor Farre-Alins, Paloma Narros-Fernandez, Melania Guerrero-Hue, Juan Antonio Moreno, Juliana M. Rosa, Jose M. Roda, Borja J. Hernandez-Garcia, Javier Egea*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Web of Science)

Abstract

Background and Purpose Ischaemic stroke is a leading cause of death, disability, and a high unmet medical need. Post-reperfusion inflammation and an up-regulation of toll-like receptor 4 (TLR4), an upstream sensor of innate immunity, are associated with poor outcome in stroke patients. Here, we identified the therapeutic effect of targeting the LPS/TLR4 signal transduction pathway. Experimental Approach We tested the effect of the TLR4 inhibitor, eritoran (E5564) in different in vitro ischaemia-related models: human organotypic cortex culture, rat organotypic hippocampal cultures, and primary mixed glia cultures. We explored the therapeutic window of E5564 in the transient middle cerebral artery occlusion model of cerebral ischaemia in mice. Key Results In vivo, administration of E5564 1 and 4 hr post-ischaemia reduced the expression of different pro-inflammatory chemokines and cytokines, infarct volume, blood-brain barrier breakdown, and improved neuromotor function, an important clinically relevant outcome. In the human organotypic cortex culture, E5564 reduced the activation of microglia and ROS production evoked by LPS. Conclusion and Implications TLR4 signalling has a causal role in the inflammation associated with a poor post-stroke outcome. Importantly, its inhibition by eritoran (E5564) provides neuroprotection both in vitro and in vivo, including in human tissue, suggesting a promising new therapeutic approach for ischaemic stroke.

Original languageEnglish
Pages (from-to)2764-2779
Number of pages16
JournalBritish Journal of Pharmacology
Volume176
Issue number15
DOIs
Publication statusPublished - Aug 2019

Keywords

  • CEREBRAL ISCHEMIA/REPERFUSION INJURY
  • CONCISE GUIDE
  • ANTAGONIST
  • ERITORAN
  • TLR4
  • PROTECTS
  • E5564
  • INHIBITION
  • ACTIVATION
  • ENDOTOXIN

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