Oleanolic acid protects against intestinal permeability defects and its causes in experimental autoimmune encephalomyelitis

Abstract

[Background]: Multiple sclerosis (MS) is a pro-inflammatory demyelinating disease of the central nervous system, in which oxidative stress also plays an important role. Accumulating evidence from studies in patients and animal models (experimental autoimmune encephalomyelitis, EAE) suggest that disruption of intestinal homeostasis may lead to disease progression, thus representing a potential therapeutic target in MS. The triterpene, oleanolic acid (OA), has proven effective protecting blood-brain barrier integrity in EAE via anti-oxidant and immunomodulatory mechanisms, therefore, its impact on intestinal barrier homeostasis deserves investigation.

[Aims]: To determine the efficacy of OA in the prevention of gut barrier alterations in EAE, with a focus on intestinal inflammatory- and oxidative-stress.

[Methods]: C57/BL6 mice were MOG35-55-inmunized and treated with OA (25 mg/kg/day, i.p) or saline. On day 21 parameters related to i) oxidative stress (O2- ions, lipid peroxidation), ii) inflammation (IL-1ß, TNFα) and iii) gut dysfunction (sCD14, intestinal fatty acid binding protein, I-FABP) were determined in serum and intestine. Studies related to intestinal permeability/structure were also performed.

[Results]: Histopathological analysis of colon showed high levels of O2- ions (DHE), mucin loss (Alcian Blue) and an altered morphology, in untreated-EAE mice, whereas these effects were not detectable in tissues from healthy or OA-treated EAE mice. Intestinal permeability analysis showed an enhancement over 5-6 fold in EAE mice compared to healthy controls (p<0.01), while in OA-treated EAE mice permeability only increased 2.5 fold (p<0.01). Accordingly, the expected high serum levels of sCD14 and I-FABP in EAE mice were prevented by OA-treatment, only increased 1.2 and 1.3 times compared to controls (p>0.05). Similarly, OA intervention abolished lipid peroxidation, and the increased IL-1ß and TNFα levels found in EAE mice (2.7±0.4pg/mg tissue and 1.2±0.7pg/mg tissue, respectively) were attenuated (1.1±0.5pg/mg tissue and 0.5±0.1pg/mg tissue, respectively) in colon of OA treated-EAE mice (p<0.001)

[Conclusion]: Our data contribute to the idea that intestinal dysfunction influences multiple sclerosis pathogenesis, and provides new findings regarding the beneficial activity of OA in EAE.