Oleanolic acid controls oxidative stress to protect against optic nerve degeneration in an experimental model of multiple sclerosis
ECTRIMS Online Library. Nieto M. Oct 11, 2014; 64109; P406
Mª Luisa Nieto
Mª Luisa Nieto
Contributions
Abstract
Background: Optic neuritis (ON) is a frequent and early symptom of multiple sclerosis (MS). ON is a condition involving inflammation, oxidative stress, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. Experimental autoimmune encephalomyelitis (EAE) is the animal model used to study MS and ON. The triterpene, oleanolic acid (OA), has proven effective in EAE via an immunomodulatory and antiinflammatory mechanism.
Objectives: Our goal was to determine the usefulness of OA in preventing ON with a focus on neuroprotection.
Methods: OA (50 mg/kg/day) was intraperitoneally administered to MOG35-55 immunized-C57/BL6 mice from immunization to day 21. Clinical score, as well as cell infiltration (hematoxylin/eosin, H&E), myelin lost (Luxol fast blue, LFB) and oxidative stress (dichlorofluorescein diacetate, DCFDA, and dihydroethidium, DHE) were analyzed in the optic nerve from untreated and OA-treated EAE mice. A RGC cell line was used to measure effectiveness of OA in vitro.
Results: High levels of ROS were detected in optic nerve sections from EAE mice, compared to healthy mice, and were strongly attenuated in samples from OA-treated EAE mice. Histopathological analysis of optic nerves showed presence of cell infiltration (H&E) and myelin loss (LFB stain) in EAE mice, whereas these effects were not detectable in tissue sections from healthy or OA-treated EAE mice. In addition, OA intervention suppressed lymphocyte proliferation (1.2+0.1, 2.6+0.4 and 1.4+0.2, in control, EAE and OA-treated EAE mice, respectively, p< 0.001). At the same time, studies in vitro showed ROS accumulation in the RGC-5 cell line by addition of 500 µM hydrogen peroxide for 24 h (23+2% of cells were positives for DCF fluorescence and 53+4% for DHE), which resulted in significant apoptotic cell loss (65+7% were stained with annexin-V). The presence of 10 µM of OA or 5 mM of NAC reduced ROS levels at resting situation (0.2% of cells positives for DCF and DHE fluorescence) and promoted cell survival (only 8+0.5% and 7.5+0.3% stained with annexin-V, respectively) in RGC-5 cells (p< 0.001).
Conclusions: OA suppressed clinical and histopathologic signs of ON preventing recruitment of inflammatory cells to the optic nerve, ameliorating production/accumulation of ROS, and restraining myelin fiber injury. Therefore OA may be a therapeutic strategy for suppressing neurodegeneration in optic neuritis.

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