title: Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia.
abstract: BACKGROUND
  The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia.
  
  
  METHODS
  We used XPro1595 (a dominant-negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated.
  
  
  RESULTS
  We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes.
  
  
  CONCLUSIONS
  Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti-TNF drugs in TNF-dependent diseases.
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. bclausen@health.sdu.dk.
authors.forename: Bettina Hjelm
authors.initials: BH
authors.lastname: Clausen
authors.affiliation: Department of Diagnostics, Molecular Sleep Laboratory, Glostrup Hospital, Nordre Ringvej 69, 2600, Glostrup, Denmark. matildadegn@gmail.com.
authors.forename: Matilda
authors.initials: M
authors.lastname: Degn
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. nmartin@health.sdu.dk.
authors.forename: Nellie Anne
authors.initials: NA
authors.lastname: Martin
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. yvonne.couch@rdm.ox.ac.uk.|Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK. yvonne.couch@rdm.ox.ac.uk.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Couch
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. lekar09@student.sdu.dk.
authors.forename: Leena
authors.initials: L
authors.lastname: Karimi
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. maorm07@student.sdu.dk.
authors.forename: Maria
authors.initials: M
authors.lastname: Ormhøj
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. malou.b.mortensen@gmail.com.
authors.forename: Maria-Louise Bergholdt
authors.initials: ML
authors.lastname: Mortensen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. hbg@sund.ku.dk.|Department of Veterinary Clinical and Animal Sciences, Facuty of Health and Medical Sciences, University of Copenhagen, Dyrlægevej 16, 1870, Frederiksberg, Denmark. hbg@sund.ku.dk.
authors.forename: Hanne Birgit
authors.initials: HB
authors.lastname: Gredal
authors.affiliation: Nuffield Department of Obstetrics and Gynecology, University of Oxford, Headley Way, OX1 3QT, Oxford, UK. chris.gardiner@obs-gyn.ox.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Gardiner
authors.affiliation: Nuffield Department of Obstetrics and Gynecology, University of Oxford, Headley Way, OX1 3QT, Oxford, UK. ian.sargent@obs-gyn.ox.ac.uk.
authors.forename: Ian I L
authors.initials: II
authors.lastname: Sargent
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 Clinical Sciences, Laboratory for Experimental Medical Science, Neuronal Survival Unit, 22100 Lund University, BMC B11, Sölveg 19, Lund, Sweden. Geraldine.Petit@med.lu.se.
authors.forename: Géraldine H
authors.initials: GH
authors.lastname: Petit
authors.affiliation: Department of Clinical Sciences, Laboratory for Experimental Medical Science, Neuronal Survival Unit, 22100 Lund University, BMC B11, Sölveg 19, Lund, Sweden. Tomas.Deierborg@med.lu.se.
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. bfinsen@health.sdu.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Finsen
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. daniel.anthony@pharm.ox.ac.uk.|Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK. daniel.anthony@pharm.ox.ac.uk.
authors.forename: Daniel Clive
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. klambertsen@health.sdu.dk.
authors.forename: Kate Lykke
authors.initials: KL
authors.lastname: Lambertsen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; C540591:XENP 1595