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Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and Upregulation of ET-1 and JNK

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Abstract

The sole FDA-approved drug treatment for ischemic stroke is tissue-type plasminogen activator (tPA). However, upregulation of JNK mitogen-activated protein kinase (MAPK) and endothelin 1 (ET-1) by tPA after stroke contributes to impaired cerebrovascular autoregulation. Wild-type (wt) tPA can bind to the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA receptors (NMDA-Rs), exacerbating vasoconstriction. Elevations in IL-6, a marker of inflammation that accompanies stroke, are reported to be an adverse prognostic factor. We hypothesized that IL-6 released into CSF after stroke by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contribute to impairment of cerebrovascular autoregulation and increased histopathology. Results show that IL-6 was increased post stroke in pigs, which was increased further by wt-tPA. Co-administration of the IL-6 antagonist LMT-28 with wt-tPA prevented impairment of cerebrovascular autoregulation and necrosis of hippocampal cells. wt-tPA co-administered with the JNK inhibitor SP 600125 and the ET-1 antagonist BQ 123 blocked stroke-induced elevation of IL-6. Co-administration of LMT-28 with wt-tPA blocked the augmentation of JNK and ET-1 post stroke. In conclusion, IL-6 released after stroke, which is enhanced by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebrovascular autoregulation and increases histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and upregulation of IL-6 may improve the benefit/risk ratio compared to wt-tPA in treatment of stroke.

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Funding

This study was funded by grants from the National Institutes of Health, NS090998 (WMA), HL76406, CA83121, HL76206, HL07971, and HL81864 (DBC), HL77760 and HL82545 (AARH), and the Israeli Science Foundation (AARH).

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, PA, 19104, USA

    William M. Armstead, Hugh Hekierski & Philip Pastor

  2. Pharmacology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    William M. Armstead

  3. Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Serge Yarovoi, Abd Al-Roof Higazi & Douglas B. Cines

  4. Department of Clinical Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Abd Al-Roof Higazi

Authors
  1. William M. Armstead
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  2. Hugh Hekierski
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  3. Philip Pastor
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  4. Serge Yarovoi
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  5. Abd Al-Roof Higazi
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  6. Douglas B. Cines
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Correspondence to William M. Armstead.

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The authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Armstead, W.M., Hekierski, H., Pastor, P. et al. Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and Upregulation of ET-1 and JNK. Transl. Stroke Res. 10, 104–111 (2019). https://doi.org/10.1007/s12975-018-0617-z

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  • DOI: https://doi.org/10.1007/s12975-018-0617-z

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