|Title:||Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase reduces brain damage and attenuates neuroinflammation after intracerebral hemorrhage||Authors:||Wu, C.-H.
|Keywords:||Soluble epoxide hydrolase; Intracerebral hemorrhage; Microglia/macrophages; Inflammation; AUDA||Issue Date:||2017||Publisher:||BIOMED CENTRAL LTD||Journal Volume:||14||Journal Issue:||1||Source:||Journal of Neuroinflammation||Abstract:||
© 2017 The Author(s). Background: Inflammatory responses significantly contribute to neuronal damage and poor functional outcomes following intracerebral hemorrhage (ICH). Soluble epoxide hydrolase (sEH) is known to induce neuroinflammatory responses via degradation of anti-inflammatory epoxyeicosatrienoic acids (EET), and sEH is upregulated in response to brain injury. The present study investigated the involvement of sEH in ICH-induced neuroinflammation, brain damage, and functional deficits using a mouse ICH model and microglial cultures. Methods: ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and sEH knockout (KO) mice. WT mice were injected intracerebroventricularly with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a selective sEH inhibitor, 30min before ICH. Expression of sEH in the hemorrhagic hemisphere was examined by immunofluorescence and Western blot analysis. The effects of genetic deletion or pharmacological inhibition of sEH by AUDA on neuroinflammatory responses, EET degradation, blood-brain barrier (BBB) permeability, histological damage, and functional deficits were evaluated. The anti-inflammatory mechanism of sEH inactivation was investigated in thrombin- or hemin-stimulated cultured microglia. Results: ICH induced an increase in sEH protein levels in the hemorrhagic hemisphere from 3h to 4days. sEH was expressed in microglia/macrophages, astrocytes, neurons, and endothelial cells in the perihematomal region. Genetic deletion of sEH significantly attenuated microglia/macrophage activation and expression of inflammatory mediators and reduced EET degradation at 1 and 4days post-ICH. Deletion of sEH also reduced BBB permeability, matrix metalloproteinase (MMP)-9 activity, neutrophil infiltration, and neuronal damage at 1 and 4days. Likewise, administration of AUDA attenuated proinflammatory microglia/macrophage activation and EET degradation at 1day post-ICH. These findings were associated with a reduction in functional deficits and brain damage for up to 28days. AUDA also ameliorated neuronal death, BBB disruption, MMP-9 activity, and neutrophil infiltration at 1day. However, neither gene deletion nor pharmacological inhibition of sEH altered the hemorrhage volume following ICH. In primary microglial cultures, genetic deletion or pharmacological inhibition of sEH by AUDA reduced thrombin- and hemin-induced microglial activation. Furthermore, AUDA reduced thrombin- and hemin-induced P38 MAPK and NF-ΚB activation in BV2 microglia cultures. Ultimately, AUDA attenuated N2A neuronal death that was induced by BV2 microglial conditioned media. Conclusions: Our results suggest that inhibition of sEH may provide a potential therapy for ICH by suppressing microglia/macrophage-mediated neuroinflammation.
|Appears in Collections:||生理學科所|
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