Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice

Hans G. Novrup, Valerie Bracchi-Ricard, Ditte G. Ellman, Jerome Ricard, Anjana Jain, Erik Runko, Lise Lyck, Minna Yli-Karjanmaa, David E. Szymkowski, Damien D. Pearse, Kate L. Lambertsen, John R Bethea

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Background: Glial cell activation and overproduction of inflammatory mediators in the central nervous system (CNS) have been implicated in acute traumatic injuries to the CNS, including spinal cord injury (SCI). Elevated levels of the proinflammatory cytokine tumor necrosis factor (TNF), which exists in both a soluble (sol) and a transmembrane (tm) form, have been found in the lesioned cord early after injury. The contribution of solTNF versus tmTNF to the development of the lesion is, however, still unclear. Methods: We tested the effect of systemically or centrally blocking solTNF alone, using XPro1595, versus using the drug etanercept to block both solTNF and tmTNF compared to a placebo vehicle following moderate SCI in mice. Functional outcomes were evaluated using the Basso Mouse Scale, rung walk test, and thermal hyperalgesia analysis. The inflammatory response in the lesioned cord was investigated using immunohistochemistry and western blotting analyses. Results: We found that peripheral administration of anti-TNF therapies had no discernable effect on locomotor performances after SCI. In contrast, central administration of XPro1595 resulted in improved locomotor function, decreased anxiety-related behavior, and reduced damage to the lesioned spinal cord, whereas central administration of etanercept had no therapeutic effects. Improvements in XPro1595-treated mice were accompanied by increases in Toll-like receptor 4 and TNF receptor 2 (TNFR2) protein levels and changes in Iba1 protein expression in microglia/macrophages 7 and 28 days after SCI. Conclusions: These studies suggest that, by selectively blocking solTNF, XPro1595 is neuroprotective when applied directly to the lesioned cord. This protection may be mediated via alteration of the inflammatory environment without suppression of the neuroprotective effects of tmTNF signaling through TNFR2.

Original languageEnglish (US)
Article number159
JournalJournal of Neuroinflammation
Volume11
Issue number1
DOIs
StatePublished - Sep 10 2014

Keywords

  • Functional outcome
  • Spinal cord injury
  • TLR4
  • TNFR2
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology

Fingerprint Dive into the research topics of 'Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice'. Together they form a unique fingerprint.

  • Cite this

    Novrup, H. G., Bracchi-Ricard, V., Ellman, D. G., Ricard, J., Jain, A., Runko, E., Lyck, L., Yli-Karjanmaa, M., Szymkowski, D. E., Pearse, D. D., Lambertsen, K. L., & Bethea, J. R. (2014). Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. Journal of Neuroinflammation, 11(1), [159]. https://doi.org/10.1186/s12974-014-0159-6