title: Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative.
abstract: OBJECTIVE
  Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO and carbamylated EPO have markedly improved functional outcome when administered after compressive SCI. However, an optimum treatment paradigm is currently unknown. Because the uninjured spinal cord expresses a high density of EPO receptor (EPOR) in the basal state, signaling through these existing receptors in advance of injury (pharmacological preconditioning) might confer neuroprotection and therefore be potentially useful in situations of anticipated damage.
  
  
  METHODS
  The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t1/2 < 2 minutes), to EPO to determine whether a single dose (10 microg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPO or EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared with animals treated with saline solution. However, pretreatment efficacy was substantially poorer than efficacy of treatment initiated at the time of injury. Serum samples drawn immediately before compression confirmed that no detectable asialoEPO remained within the systemic circulation. Western blot and immunohistochemical analyses performed using uninjured spinal cord 24 hours after a dose of asialoEPO exhibited a marked increase in glial fibrillary acidic protein, suggesting a glial response to EPO administration.
  
  
  CONCLUSIONS
  These results demonstrate that EPO and its analog do not need to be present at the time of injury to provide tissue protection and that tissue protection is markedly effective when either agent is administered immediately after injury. Furthermore, the findings suggest that asialoEPO is a useful reagent with which to study the dynamics of EPO-mediated neuroprotection. In addition, the findings support the concept of using a nonerythropoietic EPO derivative to provide tissue protection without activating the undesirable effects of EPO.
authors.affiliation: Department of Neurosurgery, University of Palermo, Italy. Giovanni.Grasso@unime.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grasso
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sfacteria
authors.forename: Serhat
authors.initials: S
authors.lastname: Erbayraktar
authors.forename: Marcello
authors.initials: M
authors.lastname: Passalacqua
authors.forename: Francesco
authors.initials: F
authors.lastname: Meli
authors.forename: Necati
authors.initials: N
authors.lastname: Gokmen
authors.forename: Osman
authors.initials: O
authors.lastname: Yilmaz
authors.forename: Domenico
authors.initials: D
authors.lastname: La Torre
authors.forename: Michele
authors.initials: M
authors.lastname: Buemi
authors.forename: Domenico G
authors.initials: DG
authors.lastname: Iacopino
authors.forename: Thomas
authors.initials: T
authors.lastname: Coleman
authors.forename: Anthony
authors.initials: A
authors.lastname: Cerami
authors.forename: Michael
authors.initials: M
authors.lastname: Brines
authors.forename: Francesco
authors.initials: F
authors.lastname: Tomasello
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001212:Asialoglycoproteins / Q000494:pharmacology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D001212:Asialoglycoproteins; D018696:Neuroprotective Agents; D017467:Receptors, Erythropoietin; C500605:asialoerythropoietin; D004921:Erythropoietin