Ribavirin reduces clinical signs and pathological changes of experimental autoimmune encephalomyelitis in Dark Agouti rats

Abstract

The effect of ribavirin on development of experimental autoimmune encephalomyelitis (EAE) was investigated. The disease was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund's adjuvant (SCH-CFA). Depending on the amount of mycobacteria in CFA, the animals developed either moderate or severe EAE. Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was applied i.p. at a daily dosage of 30 mg/kg in two treatment protocols: from the start of immunization (preventive treatment) or from the onset of the first EAE signs after the induction (therapeutic treatment). Signs of EAE began between 7 and 9 days after induction and peaked at days 11-13. In moderate EAE (mean maximal severity score 3.33 +/- 0.21), the recovery was completed by days 23-26, whereas, in severe EAE (mean maximal severity score 4.5 +/- 0.23), obvious recovery was not detected. Preventive ribavirin treatment significantly decreased clinical signs after both moderate (score 1.75 +/- 0.25, P < 0.05) and severe (score 3.62 +/- 0.31, P < 0.015) immunization. Also, disease manifestations were reduced by therapeutic treatment of ribavirin (mean maximal severity score 2.5 +/- 0.2 vs. 3.33 +/- 0.21 in controls, P < 0.005) but less so in comparison with preventive treatment. Analysis of the effects of ribavirin on histopathologic changes in the spinal cord tissue revealed a reduction of mononuclear cell infiltrates, composed of T cells and macrophages/microglia, and the absence of demyelination, which were pronounced in control EAE animals. Beneficial effects of preventive and therapeutic treatment with ribavirin on development of EAE suggest this nucleoside analogue as a useful candidate for therapy in multiple sclerosis.

The Effect of Ribavirin on Reactive Astrogliosis in Experimental Autoimmune Encephalomyelitis

“…The present study confirms our previous findings that ribavirin reduced clinical signs, inflammation, demyeli- nation, and axonal loss during EAE (20,23). Thus, our objective in the present series of experiments was to evaluate whether ribavirin would affect the astroglial response after induction of EAE in Dark Agouti rats.…”

“…In accordance with previous experiments (20,23), first signs of EAE were observed at 8 -9 days after the induction of disease in both groups, peaked at 12 -15 dpi, and the period of recovery was prolonged until 23 dpi (Fig. 1).…”

“…1). EAE rats treated with ribavirin developed a milder form of the disease, thus confirming previously demonstrated beneficial effects of the drug compared to untreated EAE rats (20,23). In addition, the group of animals that received only Complete Freund adjuvant sacrificed on 15 and 28 dpi compared to intact-physiological control revealed no statistically significant difference (data not shown).…”

“…Animals were randomly organized into the following groups (n = 6 within each group): control group (C), intact rats; EAE group, EAE was induced as described previously (20). Briefly, rats were immunized by intradermal injection of 100 μl emulsion of rat spinal cord homogenate (50% w/v in saline) and complete Freund's adjuvant containing 1 mg/ml Mycobacterium tuberculosis (Sigma, St. Louis, MO, USA) divided in half and injected in both hind footpads.…”

Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

“…Our choice of the DA rat chronic relapsing remitting model of EAE for assessment of teriflunomide is based on strong similarities in the course of disease and immunological features of the pathology in this model compared to the human disease [29]. The Dark Agouti rat strain is an EAE susceptible strain and, unlike the Lewis rat strain which can only be induced to experience a monophasic inflammatory disease when injected with guinea pig myelin antigens, this strain shows moderate to severe relapsing disease depending on the immunogen, adjuvant used, and site of injection [30,46,47].…”