Abstract
Intracerebral hemorrhage (ICH) is caused by the rupture of blood vessels in the brain. The excessive activation of glial cells and the infiltration of numerous inflammatory cells are observed during bleeding. Thrombin is a key molecule that triggers neuroinflammation in the ICH brain. In this study, we focused on lipoxin A4 (LXA4), an arachidonic acid metabolite that has been reported to suppress inflammation and cell migration. LXA4 and BML-111, an agonist of the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2), suppressed microglial activation; LXA4 strongly inhibited the migration of neutrophil-like cells in vitro. ALX/FPR2 was expressed on neutrophils in the ICH mouse brain and the daily administration of BML-111 attenuated the motor coordination dysfunction and suppressed the production of proinflammatory cytokines in the ICH mouse brain. On the other hand, BML-111 did not show a significant reduction in the number of microglia and neutrophils. These results suggest that systemic administration of ALX/FPR2 agonists may suppress the neuroinflammatory response of microglia and neutrophils without a change in cell numbers. Additionally, their combination with molecules that reduce cell numbers, such as modulators of leukotriene B4 signaling, may be required in future studies.
Highlights
Past reports showed that thrombin stimulated protease-activated receptor-1 (PAR-1) and activated microglial inflammatory reaction in the Intracerebral hemorrhage (ICH) mouse brain and in murine BV2 microglial cells
Some research reported that stimulation of the lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) expressed on microglia and macrophages
We previously provided the quantification of arachidonic acid metabolites, including lipoxin A4 (LXA4) and Leukotriene B4 (LTB4) ; LXA4 was under the detection limit in the ICH brain
Summary
Intracerebral hemorrhage (ICH) is mainly caused by hypertension and consists in the rupturing of blood vessels and leakage of blood into the brain parenchyma [1]. Severe prognoses such as motor dysfunction, sensory paralysis, and impaired consciousness are observed in patients with ICH. These lower their quality of life, with no current medical treatments being highly effective [2,3]. Microglia/macrophages release injurious molecules such as proinflammatory cytokines, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) in the ICH brain [7,8]. Ferrous ions (Fe2+ ) and heme are released by hemolysis and contribute to microglial activation [9]
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