Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice

Minna Liisa Kyllikki Yli-Karjanmaa, Bettina Hjelm Clausen, Matilda Degn, Hans Gram Novrup, Ditte Gry Ellman, Peter Toft jensen, David E. Szymkowski, Allan Stensballe, Morten Meyer, Roberta Brambilla, Kate Lykke Lambertsen*

*Corresponding author for this work

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Abstract

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/h 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 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 toward a phagocytic phenotype. Conclusion: Our data demonstrate that topical administration of XPro1595 for 3 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.

Original languageEnglish
Article number781
JournalFrontiers in Neuroscience
Volume13
Issue numberJUL
Number of pages18
ISSN1662-4548
DOIs
Publication statusPublished - Aug 2019

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Middle Cerebral Artery Infarction
Tumor Necrosis Factor-alpha
XENP 1595
Population
Etanercept
Proteins

Keywords

  • Behavior
  • Cytokines
  • Ischemic stroke
  • Microglial activation
  • Neuroprotection

Cite this

Yli-Karjanmaa, Minna Liisa Kyllikki ; Clausen, Bettina Hjelm ; Degn, Matilda ; Novrup, Hans Gram ; Ellman, Ditte Gry ; jensen, Peter Toft ; Szymkowski, David E. ; Stensballe, Allan ; Meyer, Morten ; Brambilla, Roberta ; Lambertsen, Kate Lykke. / Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice. In: Frontiers in Neuroscience. 2019 ; Vol. 13, No. JUL.
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abstract = "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/h 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 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 toward a phagocytic phenotype. Conclusion: Our data demonstrate that topical administration of XPro1595 for 3 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.",
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author = "Yli-Karjanmaa, {Minna Liisa Kyllikki} and Clausen, {Bettina Hjelm} and Matilda Degn and Novrup, {Hans Gram} and Ellman, {Ditte Gry} and jensen, {Peter Toft} and Szymkowski, {David E.} and Allan Stensballe and Morten Meyer and Roberta Brambilla and Lambertsen, {Kate Lykke}",
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Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice. / Yli-Karjanmaa, Minna Liisa Kyllikki; Clausen, Bettina Hjelm; Degn, Matilda; Novrup, Hans Gram ; Ellman, Ditte Gry; jensen, Peter Toft; Szymkowski, David E.; Stensballe, Allan; Meyer, Morten; Brambilla, Roberta; Lambertsen, Kate Lykke.

In: Frontiers in Neuroscience, Vol. 13, No. JUL, 781, 08.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Topical Administration of a Soluble TNF Inhibitor Reduces Infarct Volume After Focal Cerebral Ischemia in Mice

AU - Yli-Karjanmaa, Minna Liisa Kyllikki

AU - Clausen, Bettina Hjelm

AU - Degn, Matilda

AU - Novrup, Hans Gram

AU - Ellman, Ditte Gry

AU - jensen, Peter Toft

AU - Szymkowski, David E.

AU - Stensballe, Allan

AU - Meyer, Morten

AU - Brambilla, Roberta

AU - Lambertsen, Kate Lykke

PY - 2019/8

Y1 - 2019/8

N2 - 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/h 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 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 toward a phagocytic phenotype. Conclusion: Our data demonstrate that topical administration of XPro1595 for 3 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.

AB - 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/h 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 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 toward a phagocytic phenotype. Conclusion: Our data demonstrate that topical administration of XPro1595 for 3 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.

KW - Behavior

KW - Cytokines

KW - Ischemic stroke

KW - Microglial activation

KW - Neuroprotection

U2 - 10.3389/fnins.2019.00781

DO - 10.3389/fnins.2019.00781

M3 - Journal article

C2 - 31440125

VL - 13

JO - Frontiers in Neuroscience

JF - Frontiers in Neuroscience

SN - 1662-4548

IS - JUL

M1 - 781

ER -