TY - JOUR
T1 - Early toll-like receptor 4 blockade reduces ROS and inflammation triggered by microglial pro-inflammatory phenotype in rodent and human brain ischaemia models
AU - Parada, Esther
AU - Casas, Ana I.
AU - Palomino-Antolin, Alejandra
AU - Gomez-Rangel, Vanessa
AU - Rubio-Navarro, Alfonso
AU - Farre-Alins, Victor
AU - Narros-Fernandez, Paloma
AU - Guerrero-Hue, Melania
AU - Antonio Moreno, Juan
AU - Rosa, Juliana M.
AU - Roda, Jose M.
AU - Hernandez-Garcia, Borja J.
AU - Egea, Javier
N1 - Funding Information:
We thank Dr Lynn Hawkins for technical advice on eritoran, as well as Eisai Research Institute of Boston, Inc for their generous gift of eritoran. We also thank Instituto/Fundaci?n Te?filo Hernando for its continued support. This work was supported by grants from Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet Grants CP14/00008; PI16/00735) and Fundaci?n Mutua Madrile?a to J.E. Kootstra Talented Fellowship (UM, the Netherlands) to A.C. Grant from Roche (?Stop Fuga de Cerebros?) to J.M. Grants from Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet Grants CP10/00479 and CPII16/00017; PI13/00802; and PI14/00883), Spanish Society of Nephrology and Fundaci?n Renal I?igo Alvarez de Toledo (FRIAT), Spanish Ministry of Economy and Competitiveness (Grant RYC-2017-22369) to J.A.M. Fundacion Conchita R?bano to M.G.H.
Funding Information:
Instituto de Salud Carlos III, Grant/Award Numbers: CP10/00479, CP14/00008, CPII16/ 00017, PI13/00802, PI14/00883 and PI16/ 00735; Fundacion Conchita Rábano; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: RYC‐2017‐22369; Spanish Society of Nephrology and Fundación Renal Iñigo Alvarez de Toledo (FRIAT); Roche; Kootstra Talented Fellowship; Fundación Mutua Madrileña; Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER), Grant/Award Numbers: PI14/00883, PI13/00802, CPII16/ 00017, CP10/00479, PI16/00735 and CP14/ 00008
Funding Information:
This work was supported by grants from Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet Grants CP14/00008; PI16/00735) and Fundación Mutua Madrileña to J.E. Kootstra Talented Fellowship (UM, the Netherlands) to A.C. Grant from Roche (“Stop Fuga de Cerebros”) to J.M. Grants from Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet Grants CP10/00479 and CPII16/00017; PI13/00802; and PI14/00883), Spanish Society of Nephrology and Fundación Renal Iñigo Alvarez de Toledo (FRIAT), Spanish Ministry of Economy and Competitiveness (Grant RYC‐2017‐22369) to J.A.M. Fundacion Conchita Rábano to M.G.H.
Publisher Copyright:
© 2019 The British Pharmacological Society
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - CEREBRAL ISCHEMIA/REPERFUSION INJURY
KW - CONCISE GUIDE
KW - ANTAGONIST
KW - ERITORAN
KW - TLR4
KW - PROTECTS
KW - E5564
KW - INHIBITION
KW - ACTIVATION
KW - ENDOTOXIN
U2 - 10.1111/bph.14703
DO - 10.1111/bph.14703
M3 - Article
SN - 0007-1188
VL - 176
SP - 2764
EP - 2779
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 15
ER -