Abstract
Cytochrome P450 epoxygenase isozymes convert free arachidonic acid into eicosanoids named epoxyeicosatrienoic acids (EETs) that have roles in regulating inflammation. EETs are rapidly converted to dihydroxyeicosatrienoic acids (DiHETs) by soluble epoxide hydrolase (sEH). Little is known about the potential role of these metabolites in uveitis, but conversion of EETs to DiHETs could contribute to the inflammation. We tested a potent and orally available inhibitor of sEH for its ability to reduce ocular inflammation in a rabbit LPS-induced model of uveitis. Rabbits were treated by subcutaneous injection with the sEH inhibitor (UC1728, 3 mg/kg), or the vehicle control (PEG400) and uveitis was assessed at 6, 24 and 48 h post-intracameral LPS injection using a modified Hackett-McDonald scoring system. Eyes treated by intra-cameral injection of PBS, or by aseptic preparation served as further controls. Signs of inflammation in this model were mild and transient. Treatment with UC1728 did not significantly reduce inflammation compared to animals treated with the PEG400 vehicle. Blood levels of UC1728 were a thousand fold higher than the in vitro determined inhibitory potency (IC50) of the compound suggesting a significant degree of inhibition of sEH in the rabbit. The lack of efficacy suggests that sEH or its substrates the EETs may not be involved in mediating inflammation in this model of uveitis.
Highlights
IntroductionReviewed & Approved by: Dr Yongdong Zhou, Assistant Professor (Research) of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, USA [3,5,7,8,9]
Submission: 23 December 2015 Accepted: 07 January 2016 Published: 12 January 2016Reviewed & Approved by: Dr Yongdong Zhou, Assistant Professor (Research) of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, USA [3,5,7,8,9]
Mean blood level of trans-4-{4-[3-(4-trifluormethoxy-phenyyl)ureido]-cyclohexyloxy}-benzoic acid (UC1728) was 2070±196 nM 48 h after injection of UC1728 which is about a thousand fold above the in vitro IC50 on rabbit soluble epoxide hydrolase (sEH) arguing the lack of effect is not due to low drug levels. These results suggest that sEH, and by inference epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETs) do not play a significant role in the acute inflammation induced by endotoxin injection into the anterior chamber of rabbit eyes
Summary
Reviewed & Approved by: Dr Yongdong Zhou, Assistant Professor (Research) of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, USA [3,5,7,8,9]. These bioactive lipids are degraded by the soluble epoxide hydrolase (sEH) and converted into dihydroxyeicosatrienoic acids (DiHETs) which are thought to be pro-inflammatory. The cytochrome P450 epoxygenase-derived EETs have anti-inflammatory properties and are analgesic and anti-convulsant lipid mediators
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