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Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice

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Abstract

There are no direct evidences showing the linkage between Toll-like receptor 4 (TLR4) and blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). The purpose of this study was to examine if selective blockage of TLR4 prevents BBB disruption after SAH in mice and if the TLR4 signaling involves mitogen-activated protein kinases (MAPKs). One hundred and fifty-one C57BL/6 male mice underwent sham or endovascular perforation SAH operation, randomly followed by an intracerebroventricular infusion of vehicle or two dosages (117 or 585 ng) of a selective TLR4 antagonist IAXO-102 at 30 min post-operation. The effects were evaluated by survival rates, neurological scores, and brain water content at 24–72 h and immunoglobulin G immunostaining and Western blotting at 24 h post-SAH. IAXO-102 significantly prevented post-SAH neurological impairments, brain edema, and BBB disruption, resulting in improved survival rates. IAXO-102 also significantly suppressed post-SAH activation of a major isoform of MAPK p46 c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 as well as periostin induction and preserved tight junction protein zona occludens-1. Another selective TLR4 antagonist TAK-242, which has a different binding site from IAXO-102, also showed similar effects to IAXO-102. This study first provided the evidence that TLR4 signaling is involved in post-SAH acute BBB disruption and that the signaling is mediated at least partly by JNK activation. TLR4-targeted therapy may be promising to reduce post-SAH morbidities and mortalities.

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Acknowledgements

We thank Ms. Chiduru Yamamoto (Department of Neurosurgery, Mie University Graduate School of Medicine) for her technical assistance.

Funding

This study was funded by a Grant-in-Aid for Scientific Research from Mie Medical Research Foundation to Dr. Suzuki.

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Authors and Affiliations

  1. Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan

    Takeshi Okada, Fumihiro Kawakita, Hirofumi Nishikawa, Fumi Nakano, Lei Liu & Hidenori Suzuki

Authors
  1. Takeshi Okada
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  2. Fumihiro Kawakita
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  3. Hirofumi Nishikawa
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  4. Fumi Nakano
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  5. Lei Liu
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  6. Hidenori Suzuki
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Corresponding author

Correspondence to Hidenori Suzuki.

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The authors declare that they have no conflict of interest.

Research Involving Animals

All procedures were approved by the Animal Ethics Review Committee of Mie University and were carried out according to the institution’s Guidelines for Animal Experiments.

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Okada, T., Kawakita, F., Nishikawa, H. et al. Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice. Mol Neurobiol 56, 976–985 (2019). https://doi.org/10.1007/s12035-018-1145-2

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  • DOI: https://doi.org/10.1007/s12035-018-1145-2

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