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  • Title: Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice.
    Author: Ismael S, Nasoohi S, Yoo A, Ahmed HA, Ishrat T.
    Journal: Mol Neurobiol; 2020 Jun; 57(6):2495-2508. PubMed ID: 32172516.
    Abstract:
    Hyperglycemia has been shown to counterbalance the beneficial effects of tissue plasminogen activator (tPA) and increase the risk of intracerebral hemorrhage in ischemic stroke. Thioredoxin interacting protein (TXNIP) mediates hyperglycemia-induced oxidative damage and inflammation in the brain and reduces cerebral glucose uptake/utilization. We have recently reported that TXNIP-induced NLRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation contributes to neuronal damage after ischemic stroke. Here, we tested the hypothesis that tPA induces TXNIP-NLRP3 inflammasome activation after ischemic stroke, in hyperglycemic mice. Acute hyperglycemia was induced in mice by intraperitoneal (IP) administration of a 20% glucose solution. This was followed by transient middle cerebral artery occlusion (t-MCAO), with or without intravenous (IV) tPA administered at reperfusion. The IV-tPA exacerbated hyperglycemia-induced neurological deficits, ipsilateral edema and hemorrhagic transformation, and accentuated peroxisome proliferator activated receptor-γ (PPAR-γ) upregulation and TXNIP/NLRP3 inflammasome activation after ischemic stroke. Higher expression of TXNIP in hyperglycemic t-MCAO animals augmented glucose transporter 1 (GLUT-1) downregulation and increased vascular endothelial growth factor-A (VEGF-A) expression/matrix metallopeptidase 9 (MMP-9) signaling, all of which result in blood brain barrier (BBB) disruption and increased permeability to endogenous immunoglobulin G (IgG). It was also associated with a discernible buildup of nitrotyrosine and accumulation of dysfunctional tight junction proteins: zonula occludens-1 (ZO-1), occludin and claudin-5. Moreover, tPA administration triggered activation of high mobility group box protein 1 (HMGB-1), nuclear factor kappa B (NF-κB), and tumor necrosis factor-α (TNF-α) expression in the ischemic penumbra of hyperglycemic animals. All of these observations suggest a powerful role for TXNIP-NLRP3 inflammasome activation in the tPA-induced toxicity seen with hyperglycemic stroke.
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