Protease activated receptor-1 antagonist ameliorates the clinical symptoms of experimental autoimmune encephalomyelitis via inhibiting breakdown of blood-brain barrier.
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.
Department of Korean Medical Science, Pusan National University, Yangsan, Korea.
Ha Neui
HN
Kim
Department of Korean Medical Science, Pusan National University, Yangsan, Korea.
Yu Ri
YR
Kim
Department of Korean Medical Science, Pusan National University, Yangsan, Korea.
Sung Min
SM
Ahn
Korea Research Institute of Chemical Technology, Daejeon, Korea.
Sun Kyung
SK
Lee
Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Korea.|Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Korea.
Hwa Kyoung
HK
Shin
Department of Korean Medical Science, Pusan National University, Yangsan, Korea.|Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Yangsan, Korea.|Korean Medical Science Research Center for Healthy-Aging, Pusan National University, Yangsan, Korea.
Byung Tae
BT
Choi
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors
D007783:Lactones; D011725:Pyridines; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors
KC-A0590; SCH-530348; blood-brain barrier; experimental autoimmune encephalomyelitis; protease activated receptor-1