Erythropoietin either Prevents or Exacerbates Retinal Damage from Eye Trauma Depending on Treatment Timing.
Erythropoietin (EPO) is a promising neuroprotective agent and is currently in Phase III clinical trials for the treatment of traumatic brain injury. The goal of this study was to determine if EPO is also protective in traumatic eye injury.



The left eyes of anesthetized DBA/2J or Balb/c mice were exposed to a single 26 psi overpressure air-wave while the rest of the body was shielded. DBA/2J mice were given intraperitoneal injections of EPO or buffer and analyses were performed at 3 or 7 days post-blast. Balb/c mice were given intramuscular injections of rAAV.EpoR76E or rAAV.eGFP either pre- or post-blast and analyses were performed at 1 month post-blast.



EPO had a bimodal effect on cell death, glial reactivity, and oxidative stress. All measures were increased at 3 days post-blast and decreased at 7-days post-blast. Increased retinal ferritin and NADPH oxygenases were detected in retinas from EPO-treated mice. The gene therapy approach protected against axon degeneration, cell death, and oxidative stress when given after blast, but not before.



Systemic, exogenous EPO and EPO-R76E protects the retina after trauma even when initiation of treatment is delayed by up to 3 weeks. Systemic treatment with EPO or EPO-R76E beginning before or soon after trauma may exacerbate protective effects of EPO within the retina as a result of increased iron levels from erythropoiesis and, thus, increased oxidative stress within the retina. This is likely overcome with time as a result of an increase in levels of antioxidant enzymes. Either intraocular delivery of EPO or treatment with non-erythropoietic forms of EPO may be more efficacious.
*BA †MD ‡MA §MS ∥PhD Vanderbilt Eye Institute (CB-A, JH-B, MJ, AB-C, TSR) and Vanderbilt Brain Institute (CB-A, JH-B, TSR), Vanderbilt University Medical Center, Nashville, Tennessee; and Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee (LD'S, BL).
Courtney
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Bricker-Anthony
Lauren
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D'Surney
Brendan
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Lunn
Jessica
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Hines-Beard
Minhee
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Alexandra
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Bernardo-Colon
Tonia S
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Rex
D000818:Animals; D001753:Blast Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002470:Cell Survival; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics*; D005131:Eye Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005293:Ferritins / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D016133:Polymerase Chain Reaction; D012160:Retina / Q000293:injuries* / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors; D014786:Vision Disorders / Q000517:prevention & control; D014949:Wounds, Nonpenetrating / Q000209:etiology / Q000517:prevention & control
D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D005293:Ferritins; D019255:NADPH Oxidases