Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative

Object. Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yetbeen identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO andcarbamylated 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 ofanticipated damage.Methods. The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a briefserum half-life (t1/2 , 2 minutes), to EPO to determine whether a single dose (10 µg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determinedby a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPOor EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared withanimals 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 fibrillaryacidic 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 toprovide 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 thedynamics 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.