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

Translational Stroke Research
William M ArmsteadDouglas B Cines

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 conclu...Continue Reading

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Citations

May 23, 2019·Journal of Anesthesia·Sohei HishiyamaTakashi Matsukawa
Jul 2, 2019·Frontiers in Psychiatry·Ming-Ya LuoYi Yang
Sep 12, 2020·International Journal of Molecular Sciences·Marc Melià-SorollaTeresa Gasull
Nov 21, 2020·Translational Stroke Research·Ruiqing KangJohn H Zhang
Jun 14, 2020·CNS & Neurological Disorders Drug Targets·Yangmin ZhengYumin Luo
Jul 19, 2020·Journal of Neuroimmunology·Narayanappa AmrutaGregory Bix
May 18, 2021·Cannabis and Cannabinoid Research·Nicole L StoneSaoirse E O'Sullivan
Jun 18, 2021·American Journal of Hypertension·Jessica Youwakim, Hélène Girouard
Oct 29, 2021·Translational Stroke Research·Hidenori SuzukiMasashi Fujimoto
Jan 16, 2022·Journal of Affective Disorders·Min LiuFang Deng

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Methods Mentioned

BETA
ELISA
enzyme-linked immunosorbent assay

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