title: Intervention with an erythropoietin-derived peptide protects against neuroglial and vascular degeneration during diabetic retinopathy.
abstract: OBJECTIVE
  Erythropoietin (EPO) may be protective for early stage diabetic retinopathy, although there are concerns that it could exacerbate retinal angiogenesis and thrombosis. A peptide based on the EPO helix-B domain (helix B-surface peptide [pHBSP]) is nonerythrogenic but retains tissue-protective properties, and this study evaluates its therapeutic potential in diabetic retinopathy.
  
  
  METHODS
  After 6 months of streptozotocin-induced diabetes, rats (n = 12) and age-matched nondiabetic controls (n = 12) were evenly split into pHBSP and scrambled peptide groups and injected daily (10 μg/kg per day) for 1 month. The retina was investigated for glial dysfunction, microglial activation, and neuronal DNA damage. The vasculature was dual stained with isolectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, oxygen-induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischemia and neovascularization (1-30 μg/kg pHBSP or control peptide).
  
  
  RESULTS
  pHBSP or scrambled peptide treatment did not alter hematocrit. In the diabetic retina, Müller glial expression of glial fibrillary acidic protein was increased when compared with nondiabetic controls, but pHBSP significantly reduced this stress-related response (P < 0.001). CD11b+ microglia and proinflammatory cytokines were elevated in diabetic retina responses, and some of these responses were attenuated by pHBSP (P < 0.01-0.001). pHBSP significantly reduced diabetes-linked DNA damage as determined by 8-hydroxydeoxyguanosine and transferase-mediated dUTP nick-end labeling positivity and also prevented acellular capillary formation (P < 0.05). In OIR, pHBSP had no effect on preretinal neovascularization at any dose.
  
  
  CONCLUSIONS
  Treatment with an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathology without altering hematocrit or exacerbating neovascularization. These findings have therapeutic implications for disorders such as diabetic retinopathy.
authors.affiliation: Centre for Vision and Vascular Science, Queen’s University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: McVicar
authors.forename: Ross
authors.initials: R
authors.lastname: Hamilton
authors.forename: Liza M
authors.initials: LM
authors.lastname: Colhoun
authors.forename: Tom A
authors.initials: TA
authors.lastname: Gardiner
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Alan W
authors.initials: AW
authors.lastname: Stitt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology; D010446:Peptide Fragments / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D054730:Protein Interaction Domains and Motifs; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology
chemical_list: D016207:Cytokines; D010446:Peptide Fragments; D004921:Erythropoietin