Soluble epoxide hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis

Abstract

Background: The roles of soluble epoxide hydrolase and lipid mediators in inflammatory and neuropathic pain could be relevant in laminitis pain management.

Objectives: To determine soluble epoxide hydrolase (sEH) activity in the digital laminae, sEH inhibitor potency in vitro, and efficacy of a sEH inhibitor as an adjunct analgesic therapy in chronic laminitic horses.

Study design: In vitro experiments and clinical case series.

Methods: sEH activity was measured in digital laminae from euthanised healthy and laminitic horses (n = 5-6/group). Potency of 7 synthetic sEH inhibitors was determined in vitro using equine liver cytosol. One of them (t-TUCB; 0.1 mg/kg bwt i.v. every 24 h) was selected based on potency and stability, and used as adjunct therapy in 10 horses with severe chronic laminitis (Obel grades 2, one horse; 3-4, nine horses). Daily assessments of forelimb lifts, pain scores, physiologic and laboratory examinations were performed before (baseline) and during t-TUCB treatment. Data are presented as mean ± s.d. and 95% confidence intervals (CI).

Results: sEH activity in the digital laminae from laminitic horses (0.9±0.6 nmol/min/mg; 95% CI 0.16-1.55 nmol/min/mg) was significantly greater (P = 0.01) than in healthy horses (0.17±0.09 nmol/min/mg; CI 0.07-0.26 nmol/min/mg). t-TUCB as an adjunct analgesic up to 10 days (4.3±3 days) in laminitic horses was associated with significant reduction in forelimb lifts (36±22%; 95% CI 9-64%) and in pain scores (18±23%; 95% CI 2-35%) compared with baseline (P = 0.04). One horse developed gas colic and another corneal vascularisation in a blind eye during treatment. No other significant changes were observed.

Main limitations: Absence of control group and evaluator blinding in case series.

Conclusions: sEH activity is significantly higher in the digital laminae of actively laminitic compared with healthy horses, and use of a potent inhibitor of equine sEH as adjunct analgesic therapy appears to decrease signs of pathologic pain in laminitic horses.

Keywords: fatty acid; hoof; horse; hyperalgesia; lameness; neuropathic pain.

Figure 1

In vitro concentration-inhibitory responses of the synthetic inhibitor of soluble epoxide hydrolase (sEH), t-TUCB, using equine liver cytosol extract.

Figure 2

Percent change relative to baseline (BL) in individual pain scores during adjunct therapy with 0.1 mg/kg bwt t-TUCB intravenously every 24 hours in horses with severe chronic laminitis. Horse 1 (*) has been published as a case report (referenced removed for blinding). Panels depict the entire treatment period (A) or the first three days of treatment (B).