| Summary: | 碩士 === 國防醫學院 === 生理學研究所 === 104 === Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes, but it is associated with high mortality and morbidity. Also, there are no effective drug therapies available at present. Following ICH, danger signals from damaged neurons and blood components such as thrombin and heme trigger inflammatory processes through the MAPK-NF-κB pathway. Epoxyeicosatrienoic acids (EETs), a product of arachidonic acid metabolized through cytochrome P450, have been shown to suppress the NF-κB inflammatory pathway and reduce brain damage after brain injuries. However, EET is rapidly metabolized to less active form by soluble epoxide hydrolase (sEH). In this present study, we hypothesize that inhibition of sEH activity reduces brain damage and inflammatory reaction after experimental ICH. The mouse ICH was induced by injecting collagenase VII-S into the right striatum and the sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA, 10μM), was administered by intracerebroventricular injection. The results show that sEH protein expression increased at 1 h and lasted for 7 days following ICH, and sEH was expressed in microglia, astrocytes, and neurons. Intracerebroventricular injection with AUDA significantly improved the behavior outcomes including rotarod and beam walking latency, and mNSS for 28 days. AUDA treatment also attenuated brain atrophy at day 28 and reduced brain tissue damage and neuronal death at day 1. Furthermore, treated with AUDA attenuated the number of activated microglia, neutrophil infiltration, matrix metalloproteinase-9 (MMP-9) activity and proinflammatory cytokine production at day 1. BV2 cell line and rat microglial cell culture were used to determine if the anti-inflammatory effects of sEH inhibition directly act through microglia. AUDA attenuated LPS, IFN-γ, or thrombin -induced NO production in BV2 cell cell line or primary microglia. AUDA also attenuated proinflammatory cytokine production in primary microglia. In BV2 cell line, AUDA significantly inhibited LPS-induced p38 and pJNK phosphorylation but had no effects on Erk phosphorylation. However, treatment with AUDA did not affect the sEH level in hemorrhagic brain or LPS-stimulated microglia. These results indicate that sEH inhibition improves functional outcomes, provides neuroprotection and reduces inflammation after ICH. The anti-inflammatory effect of sEH inhibition might mediate through p38 and pJNK MAPK signaling. Inhibition of sEH may provide a novel therapeutic strategy for ICH.
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