title: Effect of a Soluble Epoxide Hydrolase Inhibitor, UC1728, on LPS-Induced Uveitis in the Rabbit.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA; Comparative Ophthalmic Research Laboratories, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA; Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Gillian J
authors.initials: GJ
authors.lastname: McLellan
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Surgical Sciences, Gazi University, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Aktas
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hennes-Beean
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Kolb
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Larsen
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Schmitz
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Hilary R
authors.initials: HR
authors.lastname: Clausius
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Wisconsin, USA; Comparative Ophthalmic Research Laboratories, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA; Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Brandt
keywords: Cytochrome P450; Inflammation; Soluble epoxide hydrolase inhibitor; UC1728; Uveitis