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

Journal of Neuroinflammation

John R Bethea³  Kate L Lambertsen⁶  Damien D Pearse⁵  David E Szymkowski¹  Minna Yli-Karjanmaa⁶  Lise Lyck⁴  Erik Runko⁵  Anjana Jain²  Jerome Ricard⁵  Ditte G Ellman⁶  Valerie Bracchi-Ricard⁵  Hans G Novrup⁶ 

[1] Xencor Inc., 111 W Lemon Ave, Monrovia 91016, CA, USA;Department of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Road, Worcester 01609-2280, MA, USA;Department of Biology, Drexel University, 3245 Chestnut St., PISB 123, Philadelphia 19104, PA, USA;Coloplast A/S, Holtedam 1, Denmark, 3050, Humlebæk, Denmark;Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami 33136, FL, USA;Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, Odense C, 5000, Denmark

关键词: Tumor necrosis factor;    TNFR2;    TLR4;    Spinal cord injury;    Functional outcome;   

Others  :  1150905
DOI  :  10.1186/s12974-014-0159-6

 received in 2014-04-16, accepted in 2014-08-23,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Novrup et al.; licensee BioMed Central Ltd.

【 图 表 】

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