The effect of novel rosmarinic acid derivative on the pathogenesis of experimental autoimmune encephalomyelitis in rats

Abstract

Rosmarinic acid is a polyphenolic compound, abundantly presentin herbs of the Lamiaceae family. The aim of the study was to evaluate a recently developed rosmarinic acid derivative (RAd), with an enhanced ability of diffusion through biological membranes 1, in preclinical settingsof the central nervous system autoimmunity. To this extent, experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was used. EAE was induced in DA rats by subcutaneous injection of autologous spinal cord homogenate 2, while treatment with RAd (30 mg/kg) started at 7 day post immunization and lasted for 15 days. Subcutaneous RAd administration successfully ameliorated EAE, leading to abbreviation of the disease duration and reducement of maximal, cumulative and meanclinical score. Also, RAd effects on draining lymph node cells (DLNC) isolated in the inductive phase of EAE and spinal cord immune cells (SCIC) obtained at the peak of the diseasewere evaluated. In vitro treatment with RAd (5 μM) reduced production of major encephalitogenic cytokines, i.e.interferon (IFN)-γ and interleukin (IL)-17, both in DLNC and SCIC. The reduction of IFN-γ and IL-17 production under the influence of RAd was also detected in the CD4+ T cells purified fromDLNC, thus suggesting that RAd had a direct effect on CD4+ T cells. Additionally, the effects of in vitro treatment with RAd were examinedon macrophages (Mf), immune cells with important role in EAE pathogenesis. Treatment of peritoneal Mf,obtained from non-immunized DA rats, with RAd (25 μM) led to reduction of NO and IL-6 production, exterted no effect on IL-1beta production, and elevated tumor necrosis factor production in Mf. Expression of MHC II and co-stimulatory molecule CD80, the phagocytic ability and the production of reactive oxygen species in RAd-treated Mf were also downregulated. Our results imply that RAd possesses anti-inflammatory and antiencephalitogenicproperties. Thus, further studies on the mechanisms behind the observed effects and their relevance for the therapy of multiple sclerosis are warranted.