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.

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.

• Authors: William M Armstead, Hugh Hekierski, Philip Pastor, Serge Yarovoi, Abd Al-Roof Higazi, Douglas B Cines
• Journal: Translational stroke research (Transl Stroke Res) Vol. 10 Issue 1 Pg. 104-111 (02 2019) ISSN: 1868-601X [Electronic] United States
• PMID: 29476447 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Endothelin-1
• Interleukin-6
• LMT-28
• Oxazolidinones
• Receptors, N-Methyl-D-Aspartate
• pyrazolanthrone
• Tissue Plasminogen Activator

Topics

• Animals
• Anthracenes (therapeutic use)
• Cerebral Cortex (physiopathology)
• Disease Models, Animal
• Endothelin-1
• Hippocampus (pathology)
• Homeostasis (physiology)
• Interleukin-6 (metabolism)
• Necrosis (etiology)
• Oxazolidinones (therapeutic use)
• Random Allocation
• Receptors, N-Methyl-D-Aspartate
• Signal Transduction
• Stroke (complications, drug therapy, metabolism, pathology)
• Swine
• Tissue Plasminogen Activator (therapeutic use)
• Up-Regulation