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Title: | Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
Author: | Griñán Ferré, Christian Companys Alemany, Júlia Jarne, Júlia Codony Gisbert, Sandra González Castillo, Celia Ortuño Sahagún, Daniel Vilageliu i Arqués, Lluïsa Grinberg Vaisman, Daniel Raúl Vázquez Cruz, Santiago Pallàs i Llibería, Mercè, 1964- |
Keywords: | Malalties de Niemann-Pick Malalties neurodegeneratives Malalties dels infants Dianes farmacològiques Niemann-Pick diseases Neurodegenerative Diseases Children's diseases Drug targeting |
Issue Date: | 26-Mar-2021 |
Publisher: | MDPI |
Abstract: | Niemann-Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts beneficial effects in modulating inflammation and autophagy, critical features of the NPC disease. This study aims to evaluate the effects of UB-EV-52, an sEH inhibitor (sEHi), in an NPC mouse model (Npc) by administering it for 4 weeks (5 mg/kg/day). Behavioral and cognitive tests (open-field test (OF)), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that the treatment produced an improvement in short- and long-term memory as well as in spatial memory. Furthermore, UB-EV-52 treatment increased body weight and lifespan by 25% and reduced gene expression of the inflammatory markers (i.e., Il-1β and Mcp1) and enhanced oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. As for autophagic markers, surprisingly, we found significantly reduced levels of LC3B-II/LC3B-I ratio and significantly reduced brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in treated Npc mice group compared to untreated ones in hippocampal tissue. Lipid profile analysis showed a significant reduction of lipid storage in the liver and some slight changes in homogenated brain tissue in the treated NPC mice compared to the untreated groups. Therefore, our results suggest that pharmacological inhibition of sEH ameliorates most of the characteristic features of NPC mice, demonstrating that sEH can be considered a potential therapeutic target for this disease. |
Note: | https://doi.org/10.3390/ijms22073409 |
It is part of: | International Journal of Molecular Sciences, 2021, vol. 22, num. 7, p. 3409 |
URI: | http://hdl.handle.net/2445/181199 |
Related resource: | https://doi.org/10.3390/ijms22073409 |
ISSN: | 1661-6596 |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Articles publicats en revistes (Genètica, Microbiologia i Estadística) Articles publicats en revistes (Biomedicina) |
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