[A Research on Drug Discovery for Intracerebral Hemorrhage Focusing on Leukotriene B4 and Its Receptor]

Abstract

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 B₄ (LTB₄) and its receptor leukotriene B₄ receptor 1 (BLT1) are proposed as novel therapeutic targets for ICH therapy. After the onset of ICH, the LTB₄ content in the brain transiently elevated. Microglia are considered as the source of LTB₄ production. Thrombin, a blood constituent, activated the BV-2 microglia and increased the LTB₄ secretion from the BV-2 cells. Microglia-released LTB₄ promoted its own microglial activation and neutrophil-like differentiated HL-60 cell migration activity. LTB₄ 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 LTB₄ receptor antagonist, attenuated neutrophil invasion, microglial activation, axonal fragmentation, and sensorimotor deficits induced by ICH. These results suggest that LTB₄ and its receptor BLT1 can be potential promising therapeutic targets that prevent tissue damages following ICH.

Keywords: intracerebral hemorrhage; leukotriene B4; microglia; neutrophil.