Neuroprotective Effects Of Erythropoietin In Mouse Models With Retinal Degeneration

Abstract

Purpose: : Programmed cell death is a hallmark of several retinal diseases such as aged-related macular degeneration and retinitis pigmentosa. We have used different mouse models of retinal degeneration that display features of the diseases in order to investigate neuroprotective properties of erythropoietin (Epo).

Methods: : C57/BL6 mice received single i.v. injections of sterile 1% NaIO₃ (25 mg/kg) to induce retinal degeneration. Control animals were treated with 0.9% NaCl. Furthermore, rds mice (O20/A-Prph2Rd2/J), an animal model of retinitis pigmentosa, were introduced. The animals were treated i.p. with Epo (Recormon 2000). NaIO₃/NaCl-injected animals received four times 100 IU, whereas rds mice were treated with 100 IU every other day between postnatal day 6 and 20. Retinal Epo contents were quantified with ¹²⁵I-Epo-based RIA. Visual acuity was measured using the OptoMotry System and scotopic and photopic electroretinograms (ERG) were recorded. Thickness of the outer nuclear layer (ONL) was measured and the number of rows of photoreceptor nuclei was counted on H&E stained paraffin sections.

Results: : RIA-analysis revealed retinal Epo overexpression of 6.1 mIU / mg protein after injections of 300 IU and 10.2 mIU / mg after injection of 600 IU Epo. NaIO₃ injected C57/BL6 displayed decreased visual acuity beginning at day 3 post injection and time-dependent decrease in ERG a-, b- and c-waves. Epo injections did not lead to significantly increased visual function compared to NaIO₃. However, in the rds mice treatment with Epo resulted in significant increases of scotopic a-, b-, and c-waves as well as photopic b-wave compared to controls. NaIO₃ induced patchy and permanent retinal pigment epithelium loss with subsequent photoreceptor damage and displayed a reduced ONL. Epo treatment did not increase the ONL thickness, as revealed by morphometric measurements. On the other hand, Epo treated rds mice showed a significant increase in ONL thickness compared to NaCl injected animals.

Conclusions: : Epo has a neuroprotective effect in the rds mouse but not in the NaIO₃ model. This indicates pathway-specific effects of Epo treatment. Because of its high safety profile and good bioavailability Epo could possibly be used for new treatment strategies in retinal degenerative diseases.

Keywords: retinal degenerations: cell biology • neuroprotection • apoptosis/cell death