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

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.

• Authors: Takeshi Okada, Fumihiro Kawakita, Hirofumi Nishikawa, Fumi Nakano, Lei Liu, Hidenori Suzuki
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 56 Issue 2 Pg. 976-985 (Feb 2019) ISSN: 1559-1182 [Electronic] United States
• PMID: 29855971 (Publication Type: Journal Article)

Chemical References

• Amino Sugars
• Glycolipids
• IAXO-102
• Toll-Like Receptor 4
• Mitogen-Activated Protein Kinases

Topics

• Amino Sugars (administration & dosage, pharmacology)
• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Glycolipids (administration & dosage, pharmacology)
• Male
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• Signal Transduction (drug effects)
• Subarachnoid Hemorrhage (drug therapy, metabolism)
• Tight Junctions (drug effects, metabolism)
• Toll-Like Receptor 4 (antagonists & inhibitors, metabolism)