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, to address its contribution to the pathological 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 and 5-lipoxygenase-activating protein was increased in the brain after ICH. Daily treatment with a 5-lipoxygenase 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 for LTB4 receptor BLT1 exhibited lower number of infiltrating neutrophils in the hematoma and lower levels of sensorimotor dysfunction after ICH than wild-type mice. Similarly, daily treatment of mice with a BLT antagonist ONO-4057 (30 or 100 mg/kg, p.o.) from 3 h 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 propose BLT1 as a promising target for ICH therapy.
- The American Society for Pharmacology and Experimental Therapeutics