Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease
| Autor: | Mercè Pallàs, Lluïsa Vilageliu, Daniel Ortuño-Sahagún, Daniel Grinberg, Sandra Codony, Celia González-Castillo, Júlia Companys-Alemany, Júlia Jarné-Ferrer, Christian Griñán-Ferré, Santiago Vázquez |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Anti-Inflammatory Agents soluble epoxide hydrolase medicine.disease_cause Antioxidants lcsh:Chemistry chemistry.chemical_compound Mice Cognition Cognitive decline Enzyme Inhibitors lcsh:QH301-705.5 Spectroscopy Epoxide Hydrolases medicine.diagnostic_test Chemistry Niemann-Pick Disease Type C General Medicine Computer Science Applications Phenotype Female medicine.symptom lifespan Epoxide hydrolase 2 Elevated plus maze medicine.medical_specialty autophagy Inflammation Catalysis Article Inorganic Chemistry Memory Internal medicine medicine Animals Physical and Theoretical Chemistry Molecular Biology sphingolipids Cholesterol Niemann–Pick type C Organic Chemistry cholesterol cognitive decline Sphingolipid Mice Inbred C57BL Endocrinology lcsh:Biology (General) lcsh:QD1-999 inflammation Lipid profile Oxidative stress |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 7 International Journal of Molecular Sciences, Vol 22, Iss 3409, p 3409 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22073409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|