title: Erythropoietin activates the phosporylated cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury.
abstract: OBJECTIVE
  Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury.
  
  
  METHODS
  Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting.
  
  
  RESULTS
  By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours.
  
  
  CONCLUSIONS
  Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Mares
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Foley
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Marshall T
authors.initials: MT
authors.lastname: Bell
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Daine T
authors.initials: DT
authors.lastname: Bennett
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Freeman
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Anesthesia, University of Colorado, Aurora, Colo.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Puskas
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colo. Electronic address: brett.reece@ucdenver.edu.
authors.forename: Thomas Brett
authors.initials: TB
authors.lastname: Reece
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010264:Paraplegia / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D020760:Spinal Cord Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D004921:Erythropoietin; C052617:Bcl2 protein, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051057:Proto-Oncogene Proteins c-akt