Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease
Por:
Griñán-Ferré C, Companys-Alemany J, Jarné-Ferrer J, Codony S, González-Castillo C, Ortuño-Sahagún D, Vilageliu L, Grinberg-Vaisman DR, Vázquez S and Pallàs M
Publicada:
1 abr 2021
Ahead of Print:
26 mar 2021
Resumen:
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-1 beta 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.
Filiaciones:
Griñán-Ferré C:
Pharmacology and Toxicology Section and Institute of Neuroscience, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
Companys-Alemany J:
Pharmacology and Toxicology Section and Institute of Neuroscience, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
Jarné-Ferrer J:
Pharmacology and Toxicology Section and Institute of Neuroscience, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
Codony S:
Laboratory of Medicinal Chemistry (CSIC, Associated Unit), Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
González-Castillo C:
Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, 45201 Jalisco, Mexico
Ortuño-Sahagún D:
Laboratorio de Neuroinmunobiología Molecular, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Jalisco 44340, Mexico
Vilageliu L:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Institut de Biomedicina de la UB (IBUB)-Institut de Recerca Sant Joan de Déu (IRSJD), 08028 Barcelona, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain
Grinberg-Vaisman DR:
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Institut de Biomedicina de la UB (IBUB)-Institut de Recerca Sant Joan de Déu (IRSJD), 08028 Barcelona, Spain
Centre for Biomedical Research on Rare Diseases (CIBERER), 08028 Barcelona, Spain
Vázquez S:
Laboratory of Medicinal Chemistry (CSIC, Associated Unit), Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
Pallàs M:
Pharmacology and Toxicology Section and Institute of Neuroscience, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain
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