title: Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice.
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.
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. hansgramnovrup@gmail.com.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Novrup
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. braccvbracchi@med.miami.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Bracchi-Ricard
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. ditdellman@health.sdu.dk.
authors.forename: Ditte G
authors.initials: DG
authors.lastname: Ellman
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. jjr325@drexel.edu.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ricard
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. A78.anjana@gmail.com.|Department of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA, 01609-2280, USA. A78.anjana@gmail.com.
authors.forename: Anjana
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. ear2105@yahoo.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Runko
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. dklilyc@coloplast.com.|Coloplast A/S, Holtedam 1, 3050, Humlebæk, Denmark, Denmark. dklilyc@coloplast.com.
authors.forename: Lise
authors.initials: L
authors.lastname: Lyck
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. mlkyli@utu.fi.
authors.forename: Minna
authors.initials: M
authors.lastname: Yli-Karjanmaa
authors.affiliation: Xencor Inc., 111 W Lemon Ave, Monrovia, CA, 91016, USA. david.szymkowski@xencor.com.
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. dpearse@med.miami.edu.
authors.forename: Damien D
authors.initials: DD
authors.lastname: Pearse
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. klambertsen@health.sdu.dk.|Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, J.B. Winsloewsvej 21 St, 5000, Odense C, Denmark. klambertsen@health.sdu.dk.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lambertsen
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Ter R-48, Miami, FL, 33136, USA. jrb445@drexel.edu.|Department of Biology, Drexel University, 3245 Chestnut St., PISB 123, Philadelphia, PA, 19104, USA. jrb445@drexel.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
mesh_terms: D000818:Animals; D005260:Female; D015918:Infusion Pumps, Implantable; D007268:Injections, Epidural; D007279:Injections, Subcutaneous; D051379:Mice; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595