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Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice

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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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Abbreviations

ASC:

Apoptosis-associated speck-like protein

BBB:

Blood brain barrier

DAMPs:

Damage-associated molecular patterns

GLUT-1:

Glucose transporter-1

HG:

Hyperglycemic

HMGB-1:

High mobility group box protein-1

HT:

Hemorrhagic transformation

IL-1β:

Interleukin 1-β

I/R:

Ischemic reperfusion

LPR:

Lipoprotein receptor–related protein

MMP:

Matrix metalloprotease

NF-κB:

Nuclear factor kappa B

NLRP3:

NOD-like receptor pyrin domain-containing-3

PAR1:

Protease activated receptor 1

PPAR-γ:

Peroxisome proliferator activated receptor-γ

TJ proteins:

Tight junction proteins

TLR:

Tol like receptor

tMCAO:

Transient middle cerebral artery occlusion

TNF-α:

Tumor necrosis factor-α

tPA:

Tissue plasminogen activator

TRX:

Thioredoxin

TXNIP:

Thioredoxin interacting protein

VEGF-A:

Vascular endothelial growth factor-A

ZO-1:

Zonula occludens-1

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Funding

This work was supported by National Institute of Health: R01-NS097800 (TI); startup funds: Department of Anatomy and Neurobiology, UTHSC Memphis TN (TI).

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-231, Memphis, TN, 38163, USA

    Saifudeen Ismael, Sanaz Nasoohi, Arum Yoo, Heba A. Ahmed & Tauheed Ishrat

  2. Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Saifudeen Ismael, Arum Yoo, Heba A. Ahmed & Tauheed Ishrat

  3. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sanaz Nasoohi

  4. Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Tauheed Ishrat

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  1. Saifudeen Ismael
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Ismael, S., Nasoohi, S., Yoo, A. et al. Tissue Plasminogen Activator Promotes TXNIP-NLRP3 Inflammasome Activation after Hyperglycemic Stroke in Mice. Mol Neurobiol 57, 2495–2508 (2020). https://doi.org/10.1007/s12035-020-01893-7

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