RETRACTED ARTICLE: Release of IL-6 After Stroke Contributes to Impaired Cerebral Autoregulation and Hippocampal Neuronal Necrosis Through NMDA Receptor Activation and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.

Propofol Ameliorates Ischemic Brain Injury by Blocking Toll-like Receptor 4-dependent Pathway and Suppressing Consequent Inflammatory Cytokine Production

“…26 Among various proin ammatory cytokines, IL-6 plays pivotal roles in local in ammation and cytotoxicity after ischemic brain injury, and is involved in the mechanism underlying the expansion of ischemic brain injury. 27,28 Blockade of IL-6 receptors has been shown to reduce infarct volume and improve cognitive function in an experimental model of ischemic stroke. 29 These earlier studies are concordant with the suppression of IL-6 by propofol observed in the current study after ischemic brain insult, as well as the reduction of infarct volume.…”

Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

“…Additionally, TNF, IL-1α, and IL-6 released by lipopolysaccharide (LPS)-activated microglia are together sufficient to induce the A1 phenotype in astrocytes [46,47]. However, studies on A2 phenotype modulation in astrocytes are still rarely reported.…”

Decreased kinesin-1 mitigates NMDA-induced exicitotoxicity and ischemia-evoked neurodegeneration

“…As such an approach would mimic intrinsic changes induced by brief and beneficial stimulations, it might be tolerated by brain and thus minimize potential side effects. This would also prolong the period before the brain becomes vulnerable to detrimental insult, enabling the brain to adapt or develop resistance (Stenzel-Poore et al, 2003), delay functional impacts like memory or motor deficits, and allow for efficient interventions (Armstead, Hekierski et al, 2018).…”