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Protease activated receptor‐1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood–brain barrier
Author(s) -
Kim Ha Neui,
Kim Yu Ri,
Ahn Sung Min,
Lee Sun Kyung,
Shin Hwa Kyoung,
Choi Byung Tae
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13285
Subject(s) - experimental autoimmune encephalomyelitis , blood–brain barrier , encephalomyelitis , immunology , multiple sclerosis , thrombin , pharmacology , medicine , receptor antagonist , receptor , antagonist , endocrinology , central nervous system , platelet
To evaluate the question of whether protease activated receptor‐1 ( PAR ‐1) antagonist is a potential therapeutic target in multiple sclerosis, we treated experimental autoimmune encephalomyelitis ( EAE ) mice with two PAR ‐1 antagonists, KC ‐A0590 and SCH ‐530348. Treatment with both antagonists resulted in a significant decrease in the clinical characteristics of EAE mice by suppressing demyelination and infiltration of inflammatory cells in the spinal cord and brain, as well as a significantly reducing the increased thrombin and tumor necrosis factor‐α. Profound leakage of dextran was observed in the brain of EAE mice. However, treatment with PAR ‐1 antagonists resulted in the stabilization of vascular endothelial cells and reduced blood–brain barrier breakdown with suppression of inflammatory response. Treatment with PAR ‐1 antagonists also resulted in down‐regulated expression of matrix metalloproteinase‐9 and preserved expression of occludin and zonula occludens ( ZO )‐1 in the brain and their significant expression was confirmed in neurons, astrocytes, and vascular endothelial cells. Finally, endothelial cells and primary cultured astrocytes were treated with PAR ‐1 antagonists; both antagonists suppressed thrombin‐induced breakdown of ZO ‐1 in endothelial cells and secretion of matrix metalloproteinase‐9 in astrocytes. Collectively, our results suggest that PAR ‐1 antagonist is effective in attenuation of the clinical symptoms of EAE mice by stabilizing the blood–brain barrier and may have therapeutic potential for treatment of multiple sclerosis.In the experimental autoimmune encephalomyelitis (EAE) mice model, treatment with two protease activated receptor‐1 (PAR‐1) antagonists KC‐A0590 and SCH‐530348 resulted in stabilization of vascular endothelial cells and reduced blood–brain barrier (BBB) breakdown with down‐regulated expression of matrix metalloproteinase‐9 (MMP‐9) and preserved expression of occludin and zonula occludens (ZO)‐1. PAR‐1 antagonist is effective in attenuation of the clinical symptoms of EAE mice by inhibiting breakdown of BBB.