Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Soluble Epoxide Hydrolase Inhibition Ameliorates Phenotype and Cognitive Capabilities in a Murine Model of Niemann Pick Disease Type C

Version 1 : Received: 5 March 2021 / Approved: 5 March 2021 / Online: 5 March 2021 (21:48:31 CET)

A peer-reviewed article of this Preprint also exists.

Griñán-Ferré, C.; Companys-Alemany, J.; Jarné-Ferrer, J.; Codony, S.; González-Castillo, C.; Ortuño-Sahagún, D.; Vilageliu, L.; Grinberg, D.; Vázquez, S.; Pallàs, M. Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease. Int. J. Mol. Sci. 2021, 22, 3409. Griñán-Ferré, C.; Companys-Alemany, J.; Jarné-Ferrer, J.; Codony, S.; González-Castillo, C.; Ortuño-Sahagún, D.; Vilageliu, L.; Grinberg, D.; Vázquez, S.; Pallàs, M. Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease. Int. J. Mol. Sci. 2021, 22, 3409.

Journal reference: Int. J. Mol. Sci. 2021, 22, 3409
DOI: 10.3390/ijms22073409

Abstract

Niemann-Pick type C (NPC) disease is a childhood autosomal recessive inherited rare neuro-degenerative disease, characterized by the accumulation of cholesterol and glycosphingolipids, implicating the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 1,2-diols, exerts beneficial effects in mod-ulating inflammation and autophagy, critical features of the NPC disease. This study aimed to evaluate the effects of UB-EV-52 a sEH inhibitor (sEHi) in the Npc mouse model by administering for 4 weeks (5 mg/kg/day). Behavioral and cognitive assays (open field test (OF), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that treatment produced an improvement in short- and long-term memory as well as in spatial memory. Moreover, the treatment with UB-EV-52 increased body weight and the lifespan by 25% and re-duced gene expression of the inflammatory markers (i.e. Il-1β and Mcp1) and improved oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. Regarding the autophagic markers, we surprisingly found significantly reduced levels of the ratio LC3B-II/LC3B-I and a significant reduction of brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in Npc mice treated group compared to non-treated. Lipid profile analysis showed a significant reduction in lipid storage in the liver and some slight changes in brain tissue in treated Npc mice compared to non-treated groups. Thus, Our results suggest that the pharmacological inhibition of sEH ameliorates most of NPC’s characteristic traits in mice, demonstrating that sEH can be considered a potential therapeutic target for this condition.

Subject Areas

Niemann-Pick type C; soluble epoxide hydrolase; autophagy; cognitive decline; lifespan; inflammation; cholesterol; sphingolipids

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