Horat, Mehmet FurkanSenol, Sefika PinarBahceli, OmerTemiz-Resitoglu, MeryemSahan-Firat, SeyhanSevim, SerhanTunctan, Bahar2025-03-172025-03-1720230145-56801165-158Xhttps://doi.org/10.14715/cmb/2023.69.10.2https://hdl.handle.net/20.500.13099/1717Soluble epoxide hydrolase (sEH) inhibition has currently emerged as a therapeutic target in the treatment of various neuroinflammatory neurodegenerative diseases, including multiple sclerosis. Previously, we reported that treatment of mice with an sEH-selective inhibitor, 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy) phenyl]urea; TPPU), ameliorated chronic experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein 35-55 peptide immunization followed by injection of pertussis toxin to mice via regulating pro-inflammatory and anti-inflammatory pathways in the central nervous system. This study tested the hypothesis that the pro-inflammatory G protein-coupled receptor (GPR) 75 and anti-apoptotic phospholipase C (PLC) signaling pathways also contribute to the ameliorating effect of TPPU on chronic EAE. Brains and spinal cords of phosphate-buffered saline-, dimethyl sulfoxide-, or TPPU (3 mg/kg)-treated mice were used for the measurement of sEH, GPR75, G alpha q/11, activator protein (AP)-1, PLC beta 4, phosphoinositide lymphoma (Bcl)-2, semaphorin (SEMA) 3A, and myelin proteolipid protein (PLP) expression and/or activity by using the immunoblotting method. Expression of sEH, GPR75, G alpha q/11, c-jun, phosphorylated c-Jun, and SEMA3A was lower, while PLC beta 4, phosphorylated PI3K p85 alpha, phosphorylated Akt1, phosphorylated MEK1/2, phosphorylated ERK1/2, phosphorylated CREB1, Bcl-2, and myelin PLP expression was higher in the tissues of TPPU (3 mg/kg)-treated mice as compared with the EAE and vehicle control groups. Inhibition of sEH by TPPU ameliorates chronic EAE through suppressing pro-inflammatory GPR75/G alpha q/11/AP-1 pathway and reducing expression of the remyelination inhibitor, SEMA3A, as well as increasing anti-apoptotic PLC/PI3K/ Akt1/MEK1/2/ERK1/2/CREB1/Bcl-2 pathway activity and myelin PLP expression.eninfo:eu-repo/semantics/openAccessExperimental autoimmune ence-phalomyelitisinflammationsoluble epoxide hydrolaseapoptosisTPPUArticle10.14715/cmb/2023.69.10.26910916Q4WOS:0011043033000072-s2.0-8517680013837953590Q4