Neuroprotection of photoreceptors by direct delivery of erythropoietin to the retina of the retinal degeneration slow mouse

Abstract

The primary objectives of this study were to determine if erythropoietin (EPO) is neuroprotective to the photoreceptors in the retinal degeneration slow (rds) mouse in the absence of an increase in hematocrit and to determine if deglycosylated EPO (DEPO) is less neuroprotective. We performed subretinal injections of 10U EPO, DEPO or hyperglycosylated EPO (HEPO) in postnatal day 7 rds mice. Whole eye EPO levels were quantified by ELISA at specified time points post-injection. TUNEL analysis, hematocrit, and immunohistochemistry were performed at postnatal day 20. Half of the amount of EPO measured immediately after injection was detected less than one hour later. Twenty four hours later, EPO levels were 1000 times lower than the amount originally detected. Uninjected rds mice contained 36±2 TUNEL-positive cells/mm retina and PBS injected mice contained 17±3 TUNEL-positive cells/mm retina. EPO, DEPO, and HEPO treated rds retinas contained 5±2, 9±2, and 3±1 TUNEL-positive cells/mm retina, respectively. The hematocrit was 43% in control and 41% in treated rds mice Previous studies have shown neuroprotection of the retina by treatment with as little as 24–39mU EPO/mg total protein in the eye. In this study, we detected 40mU/mg EPO in the eye 11 hours after injecti on of 10U EPO. Treatment with all forms of EPO tested was neuroprotective to the photoreceptors without a concomitant increase in hematocrit.

Revisiting the role of erythropoietin for treatment of ocular disorders

“…The role of EPO in neural protection by anti-apoptosis makes it an ideal treatment in ocular disorders such as AMD, 67 retinitis pigmentosa, 10 glaucoma, 68,69 optic neuritis, 30 and retinal detachment. 32 Besides that, it is able to restore proteins at the tight junction level and protect BRB.…”

“…Later, numerous studies showed evidence of EPOR expression in the inner nuclear layer (horizontal, Műller glia, bipolar, and amacrine cells) and the ganglion cell layer. 3,7,9,10 Szabo et al 11 also demonstrated that the ganglion cells principally produce and secrete EPO, which will then target and bind to the EPOR present mainly on the amacrine, horizontal, and photoreceptor cells. Another study showed that EPO expression was localized mainly in the bipolar and amacrine cells.…”

Hypoxia in the Eye: A Two-Sided Coin

“…The underlying molecular mechanisms are unclear but locally produced EPO may be part of the protection. Recombinant EPO delivered by local or systemic injections, or by viral-mediated gene transfer can provide partial protection for photoreceptors in some but not all situations (Grimm et al, 2002(Grimm et al, , 2004Rex et al, 2004Rex et al, , 2009). This may suggest that neuroprotective factors in addition to EPO are produced during or after the period of hypoxic preconditioning.…”

“…Constitutive overexpression of Epo provides some protection against light damage but not against degeneration induced by a mutation in rod opsin or a mutation in rod phosophdiesterase (Grimm et al, 2004). Direct application of EPO or systemic expression of Epo from a virally transferred gene, however, protects photoreceptors in the presence of a mutation in the peripherin gene (Rex et al, 2009;Sullivan et al, 2011).…”

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

“…1 An increasing number of studies have demonstrated the neuroprotective effects of EPO and its receptor, by anti-apoptotic mechanisms. Several studies have indicated that EPO can protect photoreceptor cells from the effects of lightinduced and hereditary retinal dystrophy; [2][3][4][5] protect retinal neurons from ischemiareperfusion injury, 6 and retinal ganglion cells after acute and chronic ocular hypertension; [7][8][9] promote ganglion cell survival and axonal regeneration after optic nerve transection; [10][11][12] attenuate inflammation in multiple sclerosis optic neuritis; 13,14 reduce the permeability of the retinal barrier and protect retinal neurons in diabetic retinopathy; [15][16][17][18] relieve diabetic macular edema; 19 enhance the stability of hypoxic retinal vessels; 20,21 and has a neuroprotective role in pigment epithelial cells subjected to photo-oxidative damage. 22 EPO exerts its biological effects through interaction with EPO receptor (EPOR).…”