TY - JOUR
T1 - Topical administration of a soluble TNF inhibitor reduces infarct volume after focal cerebral ischemia in mice
AU - Yli-Karjanmaa, Minna
AU - Clausen, Bettina Hjelm
AU - Degn, Matilda
AU - Novrup, Hans Gram
AU - Ellman, Ditte Gry
AU - Toft-Jensen, Peter
AU - Szymkowski, David E.
AU - Stensballe, Allan
AU - Meyer, Morten
AU - Brambilla, Roberta
AU - Lambertsen, Kate Lykke
N1 - Funding Information:
This work was supported by research grants from Rector's Funds (KL), the Danish Council for Independent Research (KL, DFF-4183-00033), the Lundbeck Foundation (KL, R173-2014-955), the Carlsberg Foundation (KL, 2007_01_0176), Fonden til Laegevidenskabens Fremme (MY-K), Overlaegeraadets Legatudvalg (MY-K), NIH-NINDS (RB, 1R01NS094522-01), the Italian Multiple Sclerosis Foundation (RB, FISM 2015/R/7), the US National Multiple Sclerosis Society (RB, NMSS PP-1804-30716), and The Miami Project To Cure Paralysis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD014440. We acknowledge skilled technical help from technicians Ulla Damgaard Munk and Charlotte Skouboe. RIO, University of Southern Denmark, is acknowledged for support and guidance throughout this study. Claire Gudex is acknowledged for proofreading the manuscript.
Funding Information:
This work was supported by research grants from Rector’s Funds (KL), the Danish Council for Independent Research (KL, DFF–4183-00033), the Lundbeck Foundation (KL, R173-2014-955), the Carlsberg Foundation (KL, 2007_01_0176), Fonden til Laegevidenskabens Fremme (MY-K), Overlaegeraadets Legatudvalg (MY-K), NIH-NINDS (RB, 1R01NS094522-01), the Italian Multiple Sclerosis Foundation (RB, FISM 2015/R/7), the US National Multiple Sclerosis Society (RB, NMSS PP-1804-30716), and The Miami Project To Cure Paralysis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD014440.
PY - 2019
Y1 - 2019
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
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UR - http://www.scopus.com/inward/citedby.url?scp=85070633041&partnerID=8YFLogxK
U2 - 10.3389/fnins.2019.00781
DO - 10.3389/fnins.2019.00781
M3 - Article
AN - SCOPUS:85070633041
VL - 10
JO - Frontiers in Genetics
JF - Frontiers in Genetics
SN - 1664-8021
IS - JUL
M1 - 781
ER -