title: Erythropoietin restores C-fiber function and prevents pressure ulcer formation in diabetic mice.
abstract: Pressure-induced vasodilatation (PIV), a cutaneous physiological neurovascular (C-fiber/endothelium) mechanism, is altered in diabetes and could possibly contribute to pressure ulcer development. We wanted to determine whether recombinant human erythropoietin (rhEPO), which has protective neurovascular effects, could prevent PIV alteration and pressure ulcer formation. We developed a skin pressure ulcer model in mice by applying two magnetic plates to the dorsal skin. This induced significant stage 2 ulcers (assessed visually and histologically) in streptozotocin-treated mice with 8 weeks of diabetes compared with very few in controls. Control and streptozotocin mice received either no treatment or systematic rhEPO (3,000 UI kg(-1) intraperitoneally, twice a week) during the last 2 weeks of diabetes. After 8 weeks of diabetes, we assessed ulcer development, PIV, endothelium-dependent vasodilation, C-fiber-mediated nociception threshold, and skin innervation density. Pretreatment with rhEPO fully prevented ulcer development in streptozotocin mice and also fully restored C-fiber nociception, skin innervation density, and significantly improved PIV, but had no effect on endothelium-dependent vasodilation. Our finding that rhEPO treatment protects the skin against pressure-induced ulcers in diabetic mice encourages evaluation of the therapeutic potential for non-hematopoietic analogs of EPO in preventing neuropathic diabetic ulcers.
authors.affiliation: EA 3842, Faculté de Médecine et de Pharmacie, Institut Fédératif de Recherche, Université de Limoges, Limoges, France. claire.demiot@unilim.fr
authors.forename: Claire
authors.initials: C
authors.lastname: Demiot
authors.forename: Vincent
authors.initials: V
authors.lastname: Sarrazy
authors.forename: James
authors.initials: J
authors.lastname: Javellaud
authors.forename: Loriane
authors.initials: L
authors.lastname: Gourloi
authors.forename: Laurent
authors.initials: L
authors.lastname: Botelle
authors.forename: Nicole
authors.initials: N
authors.lastname: Oudart
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Achard
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008280:Magnetics; D008297:Male; D051379:Mice; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000502:physiology*; D003668:Pressure Ulcer / Q000209:etiology* / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000294:innervation; D013311:Streptozocin / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin; D013311:Streptozocin