RESUMO
Our previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H2O2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H2O2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose , Fármacos Neuroprotetores/farmacologia , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Glutationa Peroxidase/metabolismo , Gynostemma , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/toxicidade , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/metabolismoRESUMO
AIM: To determine whether gypenosides have protective effects in experimental autoimmune optic neuritis (EAON). METHODS: Mice were randomly divided into seven groups: control group, model group, three different density gypenosides monotherapy, methylprednisolone monotherapy, combination of gypenosides and methylprednisolone group. The control group was subcutaneously injected with oil emulsion adjuvant and all other groups were subcutaneously immunized with an emulsified mixture of myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to induce EAON. Mice in the gypenosides groups were administered injections daily with three concentrations (15 mg/kg, 30 mg/kg, 45 mg/kg) of gypenosides respectively. Mice in the methylprednisolone group and the combination treatment group were injected daily with methylprednisolone (20 mg/kg) or methylprednisolone (20 mg/kg) + gypenosides (30 mg/kg), respectively. After MOG immunization, visual evoked potential (VEP), optical coherence tomography (OCT), and histopathologic examination were performed at 14, 20, 30, and 40d post-inoculation (p.i.). All results were expressed as mean±SEM. The data were evaluated by one-way ANOVA followed by Tukey or Games-Howell test. RESULTS: Compared with the control group, p2 latency was prolonged in the model group (P=0.041). Combination treatment can alleviated the change in VEP at 20d p.i. (P=0.012). Average peripapillary retinal nerve fiber layer (RNFL) thickness was reduced in the model group (P=0.000, 30d; P=0.000, 40d) and gypenosides treatment remarkably diminished the degree of RNFL degeneration at 30d and 40d p.i (P=0.000, 30d; P=0.000, 40d). The pathomorphological results showed a decrease in demye-lination (P=0.020) and inflammatory reactions in the combination group compared with the model group (20d p.i.). Gypenosides treatment also alleviated the degree of axonal loss (40d p.i.) (P=0.003). CONCLUSION: Treatment with gypenosides exerts protective effects on retinal nerve fibers and axons in EAON. When combined with gypenosides, methylprednisolone reduces demyelination in the acute stage of EAON.