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Kenneth S. Shindler, Zoe D. Fonseca-Kelly, Kimberly Dine, Tonia S. Rex; Erythropoietin Mediated Retinal Ganglion Cell Survival in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2981. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis, an inflammatory optic nerve disease, results in retinal ganglion cell (RGC) loss. Systemic erythropoietin (EPO) administration reduces RGC loss in a rat optic neuritis model, but EPO can lead to polycythemia and other side effects due to its erythropoietic effects. Recent studies showed that intramuscular injection of a vector containing a mutant form of EPO that retains its neuroprotective function but eliminates its erythropoietic effects increases RGC survival in a mouse glaucoma model. We examined whether this rAAV2/8.CMV.EpoR76E vector prevents RGC loss from optic neuritis in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis.
4 wk old C57/Bl6 mice were injected with EPO vector rAAV2/8.CMV.EpoR76E, control vector rAAV2/8.CMV.eGFP, or PBS intramuscularly in the thigh. At 8 wks, mice were immunized with myelin oligodendrocyte glycoprotein peptide to induce EAE/optic neuritis. Mice were scored daily for progressive paralysis from EAE. Visual function was measured weekly by pupillometry and optokinetic responses (OKR). 5 wks post-immunization (p.i.), RGCs were fluorogold labeled by injection in superior colliculi. Mice were sacrificed 6 wks p.i., and serum and tissues were harvested for ELISA, flow cytometry, and RGC and axonal counting.
Serum ELISA confirmed EPO expression. rAAV2/8.CMV.EpoR76E-injected mice had a small but significant delay of clinical EAE onset compared to controls, with no difference in chronic phase EAE. 6 wks p.i., RGC survival was higher in EPO treated mice as compared to control EAE mice. EPO treated mice showed delayed visual function decrease from optic neuritis measured by OKR as compared to mice that received control vector; however, by 6 wks p.i. there was no difference in OKR or pupillometry, with both EPO treated and control mice showing reduced visual function. Flow cytometric analysis of inflammatory cells isolated from spinal cords of control and treated mice revealed no differences in levels of T-cells associated with EAE pathology.
EPO reduces RGC loss in EAE optic neuritis. However, EPO does not suppress inflammation in this chronic autoimmune disease model. The limited effects of EPO on neurologic and visual function may be due to ongoing inflammation and demyelination, despite improved neuronal survival. In optic neuritis patients, inflammation usually resolves after a few weeks, while RGC loss correlates with permanent visual loss late in the disease. Neuroprotective effects of EPO therefore have the potential to enhance visual outcomes in optic neuritis if optic nerve inflammation is also treated, suggesting further studies of EPO combined with immunomodulatory therapies need to be evaluated.
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