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

• Published in: Translational stroke research 2019-02, Vol.10 (1), p.104-111
• Main Authors: Armstead, William M., Hekierski, Hugh, Pastor, Philip, Yarovoi, Serge, Higazi, Abd Al-Roof, Cines, Douglas B.
• Format: Article
• Language: English
• Subjects: Animals; Anthracenes - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cardiology; Cerebral Cortex - physiopathology; Disease Models, Animal; Endothelin-1; Hippocampus - pathology; Homeostasis - physiology; Interleukin-6 - metabolism; Necrosis - etiology; Neurology; Neurosciences; Neurosurgery; Original Article; Oxazolidinones - therapeutic use; Random Allocation; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Stroke - complications; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; Swine; Tissue Plasminogen Activator - therapeutic use; Up-Regulation; Vascular Surgery
• ISSN: 1868-4483; 1868-601X
• DOI: 10.1007/s12975-018-0617-z

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.