Effect of a Soluble Epoxide Hydrolase Inhibitor, UC1728, on LPS-Induced Uveitis in the Rabbit

Area of Science:

• Biochemistry
• Immunology
• Ophthalmology

Background:

• Cytochrome P450 epoxygenase isozymes metabolize arachidonic acid into anti-inflammatory epoxyeicosatrienoic acids (EETs).
• Soluble epoxide hydrolase (sEH) rapidly converts EETs into inactive dihydroxyeicosatrienoic acids (DiHETs).
• The role of EETs and sEH in uveitis, an inflammatory eye disease, is largely unknown.

Purpose of the Study:

• To investigate the potential role of sEH and its substrates in mediating ocular inflammation in a rabbit model of uveitis.
• To evaluate the efficacy of a potent, orally available sEH inhibitor (UC1728) in reducing inflammation in this model.

Main Methods:

• Rabbits were induced with uveitis using lipopolysaccharide (LPS) and treated with either the sEH inhibitor UC1728 or a vehicle control.
• Ocular inflammation was assessed using a modified Hackett-McDonald scoring system at 6, 24, and 48 hours post-LPS injection.
• Blood levels of UC1728 were measured to confirm sEH inhibition.

Main Results:

• The LPS-induced uveitis model exhibited mild and transient inflammatory signs.
• Treatment with UC1728 did not significantly reduce ocular inflammation compared to the vehicle control.
• Achieved blood concentrations of UC1728 were significantly higher than its in vitro inhibitory concentration, indicating effective sEH inhibition.

Conclusions:

• The lack of efficacy of the sEH inhibitor suggests that sEH and its substrates, EETs, may not be key mediators of inflammation in this rabbit model of uveitis.
• Further research is needed to elucidate the precise role of the EET pathway in ocular inflammatory diseases.