AUTHOR=Tucker Laura , Trumble Troy N. , Groschen Donna , Dobbs Erica , Baldo Caroline F. , Wendt-Hornickle Erin , Guedes Alonso G. P. 

TITLE=Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis

JOURNAL=Frontiers in Veterinary Science

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2021.685824

DOI=10.3389/fvets.2021.685824

ISSN=2297-1769

ABSTRACT=<p><bold>Objective:</bold> To determine the symptomatic and disease-modifying capabilities of sEH and COX inhibitors during joint inflammation.</p><p><bold>Methods:</bold> Using a blinded, randomized, crossover experimental design, 6 adult healthy horses were injected with lipopolysaccharide (LPS; 3 μg) from <italic>E. coli</italic> in a radiocarpal joint and concurrently received the non-selective cyclooxygenase (COX) inhibitor phenylbutazone (2 mg/kg), the sEH inhibitor <italic>t</italic>-TUCB (1 mg/kg) or both (2 mg/kg phenylbutazone and 0.1, 0.3, and 1 mg/kg <italic>t</italic>-TUCB) intravenously. There were at least 30 days washout between treatments. Joint pain (assessed <italic>via</italic> inertial sensors and peak vertical forces), synovial fluid concentrations of prostanoids (PGE<sub>2</sub>, TxB<sub>2</sub>), cytokines (IL-1β, IL-6, TNF-α) and biomarkers of collagen synthesis (CPII) and degradation (C2C) were measured at pre-determined intervals over a 48-h period. The anti-apoptotic effect of COX and sEH inhibitors was determined <italic>via</italic> ELISA technique in primary equine chondrocytes incubated with TNF-α (10 ng/ml) for 24 h. Apoptosis was also determined in chondrocytes incubated with sEH-generated metabolites.</p><p><bold>Results:</bold> Combined COX and sEH inhibition produced significantly better control of joint pain, prostanoid responses, and collagen synthesis-degradation balance compared to each compound separately. When administered separately, pain control was superior with COX <italic>vs</italic>. sEH inhibition. Cytokine responses were not different during COX and/or sEH inhibition. In cultured chondrocytes, sEH inhibition alone or combined with COX inhibition, but not COX inhibition alone had significant anti-apoptotic effects. However, sEH-generated metabolites caused concentration-dependent apoptosis.</p><p><bold>Conclusions:</bold> Combined COX and sEH inhibition optimize pain control, attenuate loss of articular cartilage matrix during joint inflammation and cytokine-induced chondrocyte apoptosis.</p>