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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00781

Topical administration of a soluble TNF inhibitor reduces infarct volume after focal cerebral ischemia in mice

 Minna Yli-Karjanmaa1,  Bettina H. Clausen1, 2,  Matilda Degn3, Hans G. Novrup1, Ditte G. Ellman1, David E. Szymkowski4,  Morten Meyer1, 2, Roberta Brambilla1, 2, 5 and  Kate L. Lambertsen1, 2, 6*
  • 1University of Southern Denmark, Denmark
  • 2Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Denmark
  • 3Paediatric Oncology Research Laboratory, Rigshospitalet, Denmark
  • 4Xencor Inc, United States
  • 5The Miami Project to Cure Paralysis, United States
  • 6Odense University Hospital, Denmark

Background: Tumor necrosis factor, which exists both as a soluble (solTNF) and a transmembrane (tmTNF) protein, plays an important role in post-stroke inflammation. The objective of the present study was to test the effect of topical versus intracerebroventricular administration of XPro1595 (a solTNF inhibitor) and etanercept (a solTNF and tmTNF inhibitor) compared to saline on output measures such as infarct volume and post-stroke inflammation in mice.
Methods: Adult male C57BL/6 mice were treated topically (2.5 mg/ml/1µl/hr for 3 consecutive days) or intracerebroventricularly (1.25 mg/kg/0.5 ml, once) with saline, XPro1595, or etanercept immediately after permanent middle cerebral artery occlusion (pMCAO). Mice were allowed to survive 1 or 3 days. Infarct volume, microglial and leukocyte profiles, and inflammatory markers were evaluated.
Results: We found that topical, and not intracerebroventricular, administration of XPro1595 reduced infarct volume at both 1 day and 3 days after pMCAO. Etanercept showed no effect. We observed no changes in microglial or leukocyte populations. XPro1595 increased gene expression of P2ry12 at 1 day and Trem2 at 1 and 3 days, while decreasing Cx3cr1 expression at 1 and 3 days after pMCAO, suggesting a change in microglial activation towards a phagocytic phenotype.
Conclusions: Our data demonstrate that topical administration of XPro1595 for three consecutive days decreases infarct volumes after ischemic stroke, while modifying microglial activation and the inflammatory response post-stroke. This suggests that inhibitors of solTNF hold great promise for future neuroprotective treatment in ischemic stroke.

Keywords: ischemic stroke, Behavior, Cytokines, microglial activation, neroprotection

Received: 28 Mar 2019; Accepted: 11 Jul 2019.

Edited by:

Mathias Gelderblom, University Medical Center Hamburg-Eppendorf, Germany

Reviewed by:

Mikhail Y. Stepanichev, Institute of Higher Nervous Activity and Neurophysiology (RAS), Russia
Qiang Liu, Barrow Neurological Institute (BNI), United States  

Copyright: © 2019 Yli-Karjanmaa, Clausen, Degn, Novrup, Ellman, Szymkowski, Meyer, Brambilla and Lambertsen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Kate L. Lambertsen, University of Southern Denmark, Odense, 5230, Denmark, klambertsen@health.sdu.dk