Article date: August 2019
By: Esther Parada, Ana I. Casas, Alejandra Palomino‐Antolin, Vanessa Gómez‐Rangel, Alfonso Rubio‐Navarro, Victor Farré‐Alins, Paloma Narros‐Fernandez, Melania Guerrero‐Hue, Juan Antonio Moreno, Juliana M. Rosa, José M. Roda, Borja J. Hernández‐García, Javier Egea in Volume 176, Issue 15, pages 2764-2779
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.
DOI: 10.1111/bph.14703
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