Deletion or inhibition of soluble epoxide hydrolase protects against brain damage and reduces microglia-mediated neuroinflammation in traumatic brain injury.

Tai-Ho Hung,Che-Feng Chang,Chun-Hu Wu,Chien-Cheng Chen,Szu-Fu Chen,Chao-Chang Lin,Song-Kun Shyue

doi:10.18632/oncotarget.21139

Abstract

Traumatic brain injury (TBI) induces a series of inflammatory processes that contribute to neuronal damage. The present study investigated the involvement of soluble epoxide hydrolase (sEH) in neuroinflammation and brain damage in mouse TBI and in microglial cultures. The effects of genetic deletion of sEH and treatment with an sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), on brain damage and inflammatory responses were evaluated in mice subjected to controlled cortical impact. The anti-inflammatory mechanism of sEH inhibition/deletion was investigated in vitro. TBI-induced an increase in sEH protein level in the injured cortex from 1 h to 4 days and sEH was expressed in microglia. Genetic deletion of sEH significantly attenuated functional deficits and brain damage up to 28 days post-TBI. Deletion of sEH also reduced neuronal death, apoptosis, brain edema, and BBB permeability at 1 and 4 day(s). These changes were associated with markedly reduced microglial/macrophage activation, neutrophil infiltration, matrix metalloproteinase-9 activity, inflammatory mediator expression at 1 and 4 day(s), and epoxyeicosatrienoic acid (EET) degradation at 1 and 4 day(s). Administration of AUDA attenuated brain edema, apoptosis, inflammatory mediator upregulation and EET degradation at 4 days. In primary microglial cultures, AUDA attenuated both LPS- or IFN-γ-stimulated nitric oxide (NO) production and reduced LPS- or IFN-γ-induced p38 MAPK and NF-κB signaling. Deletion of sEH also reduced IFN-γ-induced NO production. Moreover, AUDA attenuated N2A neuronal death induced by BV2 microglial-conditioned media. Our results suggest that inhibition of sEH may be a potential therapy for TBI by modulating the cytotoxic functions of microglia.

Highlights

Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability among young adults worldwide [1]
We investigated whether AUDA influenced the activation of mitogen-activated protein kinases (MAPKs)NF-κB, a major signaling pathway that induces a variety of proinflammation mediators in microglia during acute brain injury [30]
We show that genetic deletion of soluble epoxide hydrolase (sEH) improved long-term behavioral outcomes and attenuated brain edema in mice subjected to TBI

Summary

Introduction

Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability among young adults worldwide [1]. TBI induces brain damage due to initial physical disruption of tissue (primary injury) and subsequent development of excitotoxicity, oxidative damage, and inflammation (secondary injury) [2]. Post-traumatic inflammatory responses are mediated by activation of microglia and recruitment of peripheral leukocytes to the cerebral parenchyma [4]. Activated microglia produce multiple proinflammatory mediators, including cytokines, chemokines, nitric oxide (NO) and other factors with cytotoxic effects. Overproduction of these mediators contributes to neuronal damage and blood-brain barrier (BBB) disruption, which is considered to be the major cause of vasogenic brain edema and subsequent brain injury [3,4,5]. Inhibition of microglial activation and, production of inflammatory mediators has been suggested to be a potential therapeutic strategy for protecting the damaged brain in TBI [9, 10]

Methods

Results

Conclusion