Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats.

Jan Šilhavý,Vladimír Landa,Václav Zídek,Vojtěch Škop,Ludmila Kazdová,Hynek Strnad,Theodore Kurtz,Petr Mlejnek,Olena Oliyarnyk,Miroslava Šimáková,Michal Pravenec,Silvia C Sookoian

doi:10.1371/journal.pone.0101906

Abstract

Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

Highlights

Fumaderm is a preparation of fumaric acid esters (FAE), mainly dimethyl fumarate (DMF) and monomethyl fumarate (MMF) salts approved for treatment of psoriasis vulgaris in Germany and some neighboring countries [1]
Levels of transgenic C-reactive protein (CRP) were similar in treated versus control rats (Figure 1B) while levels of endogenous rat CRP were significantly lower in FAE treated rats than in control rats (Figure 1B)
In the current study in an animal model with inflammatory and metabolic disturbances induced by transgenic expression of human CRP, we tested the anti-inflammatory, antioxidative, and metabolic effects of Fumaderm, a preparation of fumaric acid esters containing DMF

Summary

Introduction

Fumaderm is a preparation of fumaric acid esters (FAE), mainly dimethyl fumarate (DMF) and monomethyl fumarate (MMF) salts approved for treatment of psoriasis vulgaris in Germany and some neighboring countries [1]. Owing to its immunomodulatory and anti-inflammatory effects, DMF was recently approved by the US Food and Drug Administration as a first-line therapy for adults with relapsing forms of multiple sclerosis. DMF has been explored for the treatment of other diseases including sarcoidosis, necrobiosis lipoidica or granuloma annulare and has been studied in a variety of animal models including disorders such as cancer, malaria, and Huntington disease [1]. We derived a new strain of ‘‘humanized’’ spontaneously hypertensive rats (SHR-CRP) in which transgenic expression of human C-reactive protein (CRP) in liver induces inflammation, oxidative stress, several features of metabolic syndrome, and target organ damage [3]. We explored whether FAE can exert anti-inflammatory and anti-oxidative actions associated with metabolic effects in this animal model

Methods

Results

Conclusion