Translational Stroke Research

, Volume 10, Issue 1, pp 104–111 | Cite as

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

  • William M. ArmsteadEmail author
  • Hugh Hekierski
  • Philip Pastor
  • Serge Yarovoi
  • Abd Al-Roof Higazi
  • Douglas B. Cines
Original Article


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.


Cerebral circulation Inflammatory mediators Plasminogen activators Signal transduction Ischemia 


Funding Information

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).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

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


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • William M. Armstead
    • 1
    • 2
    Email author
  • Hugh Hekierski
    • 1
  • Philip Pastor
    • 1
  • Serge Yarovoi
    • 3
  • Abd Al-Roof Higazi
    • 3
    • 4
  • Douglas B. Cines
    • 3
  1. 1.Department of Anesthesiology and Critical CareUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.PharmacologyUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of Clinical BiochemistryHebrew University-Hadassah Medical SchoolJerusalemIsrael

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