title: Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury.
abstract: OBJECTIVE
  Recombinant human erythropoietin (rhEPO) attenuated ischemia/reperfusion (I/R) injury-induced spinal cord damage. Since carbamylated EPO derivatives are stated to be devoid of rhEPO side effects, we tested the hypothesis that a newly developed carbamylated EPO-FC fusion protein (cEPO-FC) would compare favorably with rhEPO.
  
  
  METHODS
  Anesthetized and mechanically ventilated pigs randomly received cEPO-FC (50 μg kg(-1)), rhEPO (5,000 IU kg(-1)) or vehicle (n = 9 per group) 30 min prior to 30 min of aortic occlusion and over the 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80-120% of baseline values by esmolol, nitroglycerin, and adenosine-5'-triphosphate (ATP). During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Spinal cord function was assessed by motor evoked potentials (MEP) and lower limb reflexes. Tissue damage was evaluated using hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. Plasma levels of interleukin-6, tumor necrosis factor-α, and 8-isoprostanes were measured as markers of systemic inflammation and oxidative stress.
  
  
  RESULTS
  While only cEPO-FC restored MEP amplitude to values close to pre-occlusion levels, both cEPO-FC and rhEPO comparably restored lower limb reflexes and reduced the percentage of damaged neurons. Infiltration of mononuclear inflammatory cells was moderate without intergroup difference; positive TUNEL staining was barely detectable in any group. I/R injury increased blood cytokine levels without intergroup difference, whereas both cEPO-FC and rhEPO significantly lowered 8-isoprostane levels.
  
  
  CONCLUSIONS
  In a porcine model of aortic balloon occlusion-induced spinal cord I/R injury, cEPO-FC and rhEPO comparably protected against ischemic spinal cord dysfunction and neuronal damage. This effect coincided with attenuated oxidative stress.
authors.affiliation: Abteilung für Thorax- und Gefässchirurgie, Universitätsklinikum, Ulm, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Simon
authors.forename: Angelika
authors.initials: A
authors.lastname: Scheuerle
authors.forename: Michael
authors.initials: M
authors.lastname: Gröger
authors.forename: Brigitta
authors.initials: B
authors.lastname: Vcelar
authors.forename: Oscar
authors.initials: O
authors.lastname: McCook
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.forename: Enrico
authors.initials: E
authors.lastname: Calzia
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.forename: Hubert
authors.initials: H
authors.lastname: Schelzig
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000601:surgery*; D002404:Catheterization / Q000009:adverse effects*; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019054:Evoked Potentials, Motor; D015427:Reperfusion Injury / Q000209:etiology*; D020760:Spinal Cord Ischemia / Q000209:etiology*; D013552:Swine
chemical_list: C554270:EPO protein, human; C488171:carbamylated erythropoietin; D004921:Erythropoietin