Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C
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 ep...
| Autores: | , , , , , , , , , |
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| Formato: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/181199 |
| Acesso em linha: | https://hdl.handle.net/2445/181199 |
| Access Level: | acceso abierto |
| Palavra-chave: | Malalties de Niemann-Pick Malalties neurodegeneratives Malalties dels infants Dianes farmacològiques Niemann-Pick diseases Neurodegenerative Diseases Children's diseases Drug targeting |
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Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type CGriñán Ferré, ChristianCompanys Alemany, JúliaJarne Ferrer, JúliaCodony Gisbert, SandraGonzález Castillo, CeliaOrtuño Sahagún, DanielVilageliu i Arqués, LluïsaGrinberg Vaisman, Daniel RaúlVázquez Cruz, SantiagoPallàs i Llibería, Mercè, 1964-Malalties de Niemann-PickMalalties neurodegenerativesMalalties dels infantsDianes farmacològiquesNiemann-Pick diseasesNeurodegenerative DiseasesChildren's diseasesDrug targetingNiemann-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.MDPI2021info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2445/181199Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléshttps://doi.org/10.3390/ijms22073409International Journal of Molecular Sciences, 2021, vol. 22, num. 7, p. 3409https://doi.org/10.3390/ijms22073409cc-by (c) Griñán Ferré, Christian et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1811992026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| title |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| spellingShingle |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C Griñán Ferré, Christian Malalties de Niemann-Pick Malalties neurodegeneratives Malalties dels infants Dianes farmacològiques Niemann-Pick diseases Neurodegenerative Diseases Children's diseases Drug targeting |
| title_short |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| title_full |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| title_fullStr |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| title_full_unstemmed |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| title_sort |
Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C |
| dc.creator.none.fl_str_mv |
Griñán Ferré, Christian Companys Alemany, Júlia Jarne Ferrer, 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- |
| author |
Griñán Ferré, Christian |
| author_facet |
Griñán Ferré, Christian Companys Alemany, Júlia Jarne Ferrer, 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- |
| author_role |
author |
| author2 |
Companys Alemany, Júlia Jarne Ferrer, 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- |
| author2_role |
author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malalties de Niemann-Pick Malalties neurodegeneratives Malalties dels infants Dianes farmacològiques Niemann-Pick diseases Neurodegenerative Diseases Children's diseases Drug targeting |
| topic |
Malalties de Niemann-Pick Malalties neurodegeneratives Malalties dels infants Dianes farmacològiques Niemann-Pick diseases Neurodegenerative Diseases Children's diseases Drug targeting |
| description |
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. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/181199 |
| url |
https://hdl.handle.net/2445/181199 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
https://doi.org/10.3390/ijms22073409 International Journal of Molecular Sciences, 2021, vol. 22, num. 7, p. 3409 https://doi.org/10.3390/ijms22073409 |
| dc.rights.none.fl_str_mv |
cc-by (c) Griñán Ferré, Christian et al., 2021 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by (c) Griñán Ferré, Christian et al., 2021 https://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI |
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MDPI |
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Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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