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J Neuroinflammation. 2014 Dec 12;11:203. doi: 10.1186/s12974-014-0203-6.

Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia.

Author information

1
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. bclausen@health.sdu.dk.
2
Department of Diagnostics, Molecular Sleep Laboratory, Glostrup Hospital, Nordre Ringvej 69, 2600, Glostrup, Denmark. matildadegn@gmail.com.
3
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. nmartin@health.sdu.dk.
4
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.
5
Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK. yvonne.couch@rdm.ox.ac.uk.
6
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. lekar09@student.sdu.dk.
7
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. maorm07@student.sdu.dk.
8
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.
9
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. hbg@sund.ku.dk.
10
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.
11
Nuffield Department of Obstetrics and Gynecology, University of Oxford, Headley Way, OX1 3QT, Oxford, UK. chris.gardiner@obs-gyn.ox.ac.uk.
12
Nuffield Department of Obstetrics and Gynecology, University of Oxford, Headley Way, OX1 3QT, Oxford, UK. ian.sargent@obs-gyn.ox.ac.uk.
13
Xencor Inc, 111 W Lemon Ave, Monrovia, CA, 91016, USA. david.szymkowski@xencor.com.
14
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.
15
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.
16
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. bfinsen@health.sdu.dk.
17
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.
18
Department of Pharmacology, University of Oxford, Mansfield Road, OX1 3QT, Oxford, UK. daniel.anthony@pharm.ox.ac.uk.
19
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st., 5000, Odense, Denmark. klambertsen@health.sdu.dk.

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.

PMID:
25498129
PMCID:
PMC4272527
DOI:
10.1186/s12974-014-0203-6
[Indexed for MEDLINE]
Free PMC Article

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