Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury

^*Pharmacological Laboratories, Departments of Medicine, Surgery, and Dentistry, Polo Ospedale San Paolo, Faculty of Medicine, Via A. di Rudinì 8 and ^†Department of Biomolecular Sciences and Biotechnology, Faculty of Sciences, University of Milan, Via Celoria 26, 20133 Milan, Italy; and ^‡The Kenneth S. Warren Institute, Ossining, NY 10562

Contributed by Anthony Cerami, September 28, 2005

Abstract

Inflammation plays a major pathological role in spinal cord injury (SCI). Although antiinflammatory treatment using the glucocorticoid methyprednisolone sodium succinate (MPSS) improved outcomes in several multicenter clinical trials, additional clinical experience suggests that MPSS is only modestly beneficial in SCI and poses a risk for serious complications. Recent work has shown that erythropoietin (EPO) moderates CNS tissue injury, in part by reducing inflammation, limiting neuronal apoptosis, and restoring vascular autoregulation. We determined whether EPO and MPSS act synergistically in SCI. Using a rat model of contusive SCI, we compared the effects of EPO [500-5,000 units/kg of body weight (kg-bw)] with MPSS (30 mg/kg-bw) for proinflammatory cytokine production, histological damage, and motor function at 1 month after a compression injury. Although high-dose EPO and MPSS suppressed proinflammatory cytokines within the injured spinal cord, only EPO was associated with reduced microglial infiltration, attenuated scar formation, and sustained neurological improvement. Unexpectedly, coadministration of MPSS antagonized the protective effects of EPO, even though the EPO receptor was up-regulated normally after injury. These data illustrate that the suppression of proinflammatory cytokines alone does not necessarily prevent secondary injury and suggest that glucocorticoids should not be coadministered in clinical trials evaluating the use of EPO for treatment of SCI.

Footnotes

↵ § To whom correspondence may be addressed at: The Kenneth S. Warren Institute, 712 Kitchawan Road, Ossining, NY 10562. E-mail: mbrines{at}kswi.org or lkinaj{at}warrenpharma.com
Author contributions: A.G., A.C., and M.B. designed research; A.G., L.M., B.D.S., S.C., A.M.D.G., S.D.B., T.C., and M.B. performed research; A.G., L.M., B.D.S., S.C., A.M.D.G., S.D.B., T.C., and M.B. analyzed data; and A.G., T.C., A.C., and M.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations: EPO, erythropoietin; EPOR, EPO receptor; GFAP, glial fibrillary acidic protein; kg-bw, kg of body weight; MPSS, methylprednisolone sodium succinate; rhEPO, recombinant human EPO; MIP, macrophage inflammatory protein; SCI, spinal cord injury.