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Introduction: The sole FDA approved drug treatment for acute stroke is tissue type plasminogen activator (tPA). However, its brief therapeutic window and post-treatment complications markedly constrain its use. Upregulation of JNK MAPK and ET-1 by exogenous tPA after thrombotic stroke contributes to impaired cerebrovascular autoregulation, which exacerbates ischemic injury. Wild type (wt) tPA can bind to either the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA-receptors (NMDA-Rs), exacerbating vasoconstriction and ischemia. tPA-A296-299, a variant that is fibrinolytic and binds to LRP but not to NMDA-Rs, does not induce upregulation of ET-1 and JNK and thereby does not exacerbate loss of autoregulation and the resultant histopathology after stroke. Elevations in IL-6, a marker of the inflammation that accompanies ischemic stroke, is reported to be an adverse prognostic factor.Hypothesis: We hypothesized that IL-6 released after stroke by wt tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contributes to impairment of cerebral autoregulation and increased histopathology.Methods: Pial artery diameter, CSF ET-1, JNK, and IL-6 measured and histopathology assessed in anesthetized pigs. Stroke was induced by photothrombosis.Results: IL-6 was increased post-stroke, which was increased further by wt tPA. Co-administration of the IL-6 antagonist LMT-28 with wt tPA prevented impairment of cerebral autoregulation and necrosis of hippocampal CA1, CA3 cells. Isoproterenol dilation was unchanged by stroke. tPA-A296-299, 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.Conclusions: IL-6 released after stroke, which is enhanced by wt tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebral autoregulation and increased histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and release of IL-6, such as tPA-A296-299, may improve the benefit/risk ratio compared to wt tPA in treatment of stroke.