Abstract
We aimed to determine the effect of soluble epoxide hydrolase (sEH) inhibition on chronic experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), associated with changes in inflammasome-dependent and -independent inflammatory and anti-inflammatory pathways in the CNS of mice. C57BL/6 mice were used to induce chronic EAE by using an injection of MOG35–55 peptide/PT. Animals were observed daily and scored for EAE signs for 25 days after immunization. Following the induction of EAE, the scores were increased after 9 days and reached peak value as determined by ≥ 2 or ≤ 3 with 8% mortality rate on day 17. On day 17, mice were administered daily PBS, DMSO, or TPPU (a potent sEH inhibitor) (1, 3, or 10 mg/kg) until the end of the study. TPPU only at 3 mg/kg dose decreased the AUC values calculated from EAE scores obtained during the disease compared to EAE and vehicle control groups. On day 25, TPPU also caused an increase in the PPARα/β/γ and NLRC3 proteins and a decrease in the proteins of TLR4, MyD88, NF-κB p65, p-NF-κB p65, iNOS/nNOS, COX-2, NLRC4, ASC, caspase-1 p20, IL-1β, caspase-11 p20, NOX subunits (gp91phox and p47phox), and nitrotyrosine in addition to 14,15-DHET and IL-1β levels compared to EAE and vehicle control groups. Our findings suggest that pharmacological inhibition of sEH attenuates chronic EAE likely because of enhanced levels of anti-inflammatory EETs in addition to PPARα/β/γ and NLRC3 expression associated with suppressed inflammatory TLR4/MyD88/NF-κB signalling pathway, NLRC4/ASC/pro-caspase-1 inflammasome, caspase-11 inflammasome, and NOX activity that are responsible for inflammatory mediator formation in the CNS of mice.
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Acknowledgements
This study was financially supported by a grant from Mersin University (2019-1-TP2-3142). The results presented in this study were included in the Master’s Thesis of Pharm. M.S. Merve Biliktu.
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Biliktu, M., Senol, S.P., Temiz-Resitoglu, M. et al. Pharmacological inhibition of soluble epoxide hydrolase attenuates chronic experimental autoimmune encephalomyelitis by modulating inflammatory and anti-inflammatory pathways in an inflammasome-dependent and -independent manner. Inflammopharmacol 28, 1509–1524 (2020). https://doi.org/10.1007/s10787-020-00691-w
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DOI: https://doi.org/10.1007/s10787-020-00691-w