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Effect of Interferon-β on Neuroinflammation, Brain Injury and Neurological Outcome After Experimental Subarachnoid Hemorrhage

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Abstract

Introduction

Aneurysmal subarachnoid hemorrhage (SAH) has a poor outcome, particularly attributed to progressive injury after the initial incident. Several studies suggest a critical role for inflammation in lesion progression after SAH. Our goal was to test whether treatment with anti-inflammatory interferon-β, which has shown promise as a therapeutic agent in experimental ischaemic stroke, can protect the brain after SAH.

Methods

SAH was induced in adult male Wistar rats by puncturing the intracranial bifurcation of the right internal carotid artery. Treatment effects of daily interferon-β (n = 16) or vehicle (n = 14) injections were serially evaluated with multiparametric MRI and behavioral tests from day 0 to 7, in compliance with recent recommendations for pre-clinical drug testing. Outcome measures included neurological status, brain lesion volume, blood–brain barrier (BBB) leakage, and levels of inflammatory markers.

Results

In animals that survived up to 7 days post-SAH, we found no significant differences between vehicle- and interferon-β-treated animals with respect to final neurological score (14.3 ± 1.0 vs. 13.0 ± 2.2), brain lesion size on T2-weighted MR images (59 ± 83 vs. 124 ± 99 mm3), BBB leakage (0.26 ± 0.05 vs. 0.22 ± 0.08 contrast-induced relative MR signal change), upregulation of brain RNA for cytokines, chemokines and cell adhesion molecules, and increased neutrophil activation.

Conclusions

In contrast to previously published findings in experimental ischemic stroke models, interferon-β has no clear efficacy to protect the brain after SAH. In line with recent highlighting of the significance of negative findings, our data currently do not recommend clinical testing of interferon-β to prevent neurological damage in SAH patients.

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Acknowledgments

This research was conducted with financial aid from The Netherlands Brain Foundation (15F07(2)0.08), The Netherlands Heart Foundation (2005B156) and the University Medical Centre Utrecht. Interferon-β was provided by U-CyTech.

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Authors and Affiliations

  1. Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands

    Ivo A. C. W. Tiebosch, Rick M. Dijkhuizen, Mark J. R. J. Bouts & René Zwartbol

  2. Department of Intensive Care Medicine, Room Q04.460, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    Pieter M. Cobelens & Walter M. van den Bergh

  3. Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Utrecht, The Netherlands

    Pieter M. Cobelens

  4. Cytokine Biology Unit, Central Laboratory Animal Institute, Utrecht University, Utrecht, The Netherlands

    Peter H. van der Meide

Authors
  1. Ivo A. C. W. Tiebosch
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  2. Rick M. Dijkhuizen
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  3. Pieter M. Cobelens
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  4. Mark J. R. J. Bouts
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  5. René Zwartbol
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  6. Peter H. van der Meide
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  7. Walter M. van den Bergh
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Corresponding author

Correspondence to Walter M. van den Bergh.

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Tiebosch, I.A.C.W., Dijkhuizen, R.M., Cobelens, P.M. et al. Effect of Interferon-β on Neuroinflammation, Brain Injury and Neurological Outcome After Experimental Subarachnoid Hemorrhage. Neurocrit Care 18, 96–105 (2013). https://doi.org/10.1007/s12028-012-9692-2

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  • DOI: https://doi.org/10.1007/s12028-012-9692-2

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