PT - JOURNAL ARTICLE AU - Masanori Hijioka AU - Junpei Anan AU - Hayato Ishibashi AU - Yuki Kurauchi AU - Akinori Hisatsune AU - Takahiro Seki AU - Tomoaki Koga AU - Takehiko Yokomizo AU - Takao Shimizu AU - Hiroshi Katsuki TI - Inhibition of Leukotriene B<sub>4</sub> Action Mitigates Intracerebral Hemorrhage-Associated Pathological Events in Mice AID - 10.1124/jpet.116.238824 DP - 2017 Mar 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 399--408 VI - 360 IP - 3 4099 - http://jpet.aspetjournals.org/content/360/3/399.short 4100 - http://jpet.aspetjournals.org/content/360/3/399.full SO - J Pharmacol Exp Ther2017 Mar 01; 360 AB - Infiltration of neutrophils has been suggested to play an important role in the pathogenesis of intracerebral hemorrhage (ICH) for which effective therapeutic interventions remain unavailable. In the present study we focused on leukotriene B4 (LTB4) as a potent chemotactic factor for neutrophils in order to address its contribution to the pathologic events associated with ICH. ICH with hematoma expansion into the internal capsule that resulted in severe sensorimotor dysfunction was induced by injection of collagenase in mouse striatum. We found that LTB4 as well as mRNAs of 5-lipoxygenase (5-LOX) and 5-LOX-activating protein were increased in the brain after ICH. Daily treatment with a 5-LOX inhibitor zileuton (3 or 10 mg/kg, i.v.) prevented ICH-induced increase in LTB4, attenuated neutrophil infiltration into the hematoma, and ameliorated sensorimotor dysfunction. In addition, mice deficient in LTB4 receptor BLT1 exhibited a lower number of infiltrating neutrophils in the hematoma and lower levels of sensorimotor dysfunction after ICH than did wild-type mice. Similarly, daily treatment of mice with BLT antagonist ONO-4057 (30 or 100 mg/kg, by mouth) from 3 hours after induction of ICH inhibited neutrophil infiltration and ameliorated sensorimotor dysfunction. ONO-4057 also attenuated inflammatory responses of microglia/macrophages in the perihematoma region and axon injury in the internal capsule. These results identify LTB4 as a critical factor that plays a major role in the pathogenic events in ICH, and BLT1 is proposed as a promising target for ICH therapy.