[A Research on Drug Discovery for Intracerebral Hemorrhage Focusing on Leukotriene B and Its Receptor].

Intracerebral hemorrhage (ICH) results from blood vessels rupture in the brain, forming a blood clot in the brain parenchyma. Leakage of blood constituents causes detrimental tissue damages, ensuing long-lasting neurological deficits; however, effective therapeutic approaches are not yet developed to date. In this study, leukotriene B (LTB) and its receptor leukotriene B receptor 1 (BLT1) are proposed as novel therapeutic targets for ICH therapy. After the onset of ICH, the LTB content in the brain transiently elevated. Microglia are considered as the source of LTB production. Thrombin, a blood constituent, activated the BV-2 microglia and increased the LTB secretion from the BV-2 cells. Microglia-released LTB promoted its own microglial activation and neutrophil-like differentiated HL-60 cell migration activity. LTB receptors comprised of two types: BLT1 and BLT2, with BLT1 known to be a high-affinity receptor associated with chemotaxis. BLT1 knockout mice showed decreased neutrophil invasion, attenuating sensorimotor dysfunction after ICH. Furthermore, therapeutic administration of ONO-4057, an orally active LTB receptor antagonist, attenuated neutrophil invasion, microglial activation, axonal fragmentation, and sensorimotor deficits induced by ICH. These results suggest that LTB and its receptor BLT1 can be potential promising therapeutic targets that prevent tissue damages following ICH.