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

Christian Griñán-Ferré,Daniel Grinberg,Lluïsa Vilageliu,Santiago Vázquez,Mercè Pallàs,Júlia Companys-Alemany,Sandra Codony,Júlia Jarné-Ferrer,Celia González-Castillo,Daniel Ortuño-Sahagún

doi:10.3390/ijms22073409

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.

Highlights

Niemann–Pick disease type C (NPC, MIM # 257220) is a rare autosomal recessive neurodegenerative disease (1/120,000 live births in Europe)
From baseline (1 week of age), NPC mouse model (Npc) mice were significantly lower compared to wild-type (Wt) mice, whereas UB-EV52 treatment significantly increased the bodyweight of Npc mice (Figure 1C)
This study focuses on establishing a relationship between cognitive improvement, anti-inflammatory and antioxidant effects and the reduction of the autophagic process in the brain of the Niemann–Pick type C (NPC) mouse model after treatment with UB-EV-52, a well-known, potent and specific sEH inhibitor (sEHi) [21]

Summary

Introduction

Niemann–Pick disease type C (NPC, MIM # 257220) is a rare autosomal recessive neurodegenerative disease (1/120,000 live births in Europe). The disorder is characterized by a defect in lipid trafficking that results in an inability to process cellular cholesterol, accompanied by a secondary accumulation of glycosphingolipids in the lysosomes of affected individuals [1,2]. It is caused by mutations in the NPC1 gene (this occurs in 95% of diagnosed cases) or in the NPC2 gene [3]. Adult manifestation (15 years and older) is rare, progression is usually much slower, and patients present with a broad phenotypic spectrum similar to childhood manifestation, including epilepsy and parkinsonism syndrome. Disease progression and life expectancy are causally related to the occurrence of neurological symptoms [5]

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