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Journal article
Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice
Journal of neuroinflammation, v 11(1), pp 159-159
10 Sep 2014
PMID: 25204558
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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.
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.
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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Details
- Title
- Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice
- Creators
- Hans G Novrup - University of Southern DenmarkValerie Bracchi-Ricard - University of MiamiDitte G Ellman - University of Southern DenmarkJerome Ricard - University of MiamiAnjana Jain - University of MiamiErik Runko - Miami Project to Cure ParalysisLise Lyck - University of Southern DenmarkMinna Yli-Karjanmaa - Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. mlkyli@utu.fiDavid E Szymkowski - XencorDamien D Pearse - Miami Project to Cure ParalysisKate L Lambertsen - University of MiamiJohn R Bethea - Drexel University
- Publication Details
- Journal of neuroinflammation, v 11(1), pp 159-159
- Publisher
- Springer BMC
- Grant note
- NS051709-06 / NINDS NIH HHS R01 NS051709 / NINDS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000342697200002
- Scopus ID
- 2-s2.0-84908137998
- Other Identifier
- 991019167812404721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Immunology
- Neurosciences