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Alan W. Stitt, Carmel McVicar, Ross Hamilton, Liza Colhoun, Tom Gardiner, Michael Brines, Anthony Cerami; Intervention With A Novel, Erythropoietin-derived Peptide Protects Against Neuroglial And Vascular Degeneration During Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3560.
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Erythropoietin (EPO) shows anti-inflammatory and anti-apoptotic properties although there are concerns that therapeutic could cause thrombotic events and inappropriate neovascularisation. A novel peptide based on the EPO helix-B domain (pHBSP) is non-erythrogenic but retains tissue protective properties. Diabetic retinopathy is characterised by early-phase neurovascular degenerative pathology and late-stage ischaemia-driven neovascularisation. This study has evaluated the potential of pHBSP to protect the retina from diabetes-related damage without exacerbating sight-threatening proliferative diabetic retinopathy.
Streptozotocin (STZ)-induced diabetes was maintained in rats for 6 months. Diabetic (n=12) and age-matched non-diabetic control (n=12) rats were then evenly split into pHBSP and control peptide groups and injected daily (10µg/kg; i.p.) for 1 month. The retina was investigated for glial dysfunction, microglial activation and neuronal apoptosis using GFAP, CD11b and TUNEL labelling respectively. The retinal vasculature was also assessed using confocal microscopy of flat-mounts dual-stained with lectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, a murine model of oxygen induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischaemia and neovascularisation. Mice received 5 daily doses of 1, 10 or 30µg/kg (i.p.) pHBSP or control peptide.
pHBSP or scrambled peptide treatment had no significant influence on haemocrit. In the retina, diabetes induced Müller glial expression of GFAP when compared to non-diabetic controls but pHBSP significantly reduced this stress-related response (p<0.001). CD11b+ microglia were increased in diabetic retina and showed amoeboid (active) morphology and this was attenuated by pHBSP (p<0.01). Diabetic retina showed many TUNEL positive cells and pHBSP significantly reduced this apoptotic response (p<0.05) and also prevented acellular capillary formation (p<0.05). In OIR, pHBSP had no effect on pre-retinal neovascularisation at any dose.
Systemic delivery of an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathology, without altering haemocrit or exacerbating neovascularisation. These findings have therapeutic implications for preventing major sight-threatening disorders such as diabetic retinopathy.
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