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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2014

Open Access 01-12-2014 | Research

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

Authors: 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

Published in: Journal of Neuroinflammation | Issue 1/2014

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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.
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Metadata
Title
Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice
Authors
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
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2014
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-014-0159-6

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