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Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome
  • +3
  • Saifudeen Ismael,
  • Sanaz Nasoohi,
  • ARum Yoo,
  • Golnousg Mirzahosseini,
  • Heba Ahmed,
  • Tauheed Ishrat
Saifudeen Ismael
UTHSC Memphis
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Sanaz Nasoohi
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences
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ARum Yoo
UTHSC Memphis
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Golnousg Mirzahosseini
UTHSC College of Pharmacy
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Heba Ahmed
UTHSC Memphis
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Tauheed Ishrat
UTHSC College of Pharmacy
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Peer review status:UNDER REVIEW

11 Jun 2020Submitted to British Journal of Pharmacology
13 Jun 2020Assigned to Editor
13 Jun 2020Submission Checks Completed
18 Jun 2020Reviewer(s) Assigned

Abstract

Background and Purpose: Thrombolytic therapy has remained utterly challenging in hyperglycemic patients for poor prognosis and increased hemorrhagic conversions. We have recently shown that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, as an established TXNIP inhibitor may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Experimental approach: Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were tested for neurobehavioral deficits followed by evaluation of infarct size, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. Key results: As an adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metallopeptidase 9 (MMP-9), and tight junction protein deregulation, all leading to less hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NRRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation, along with reduced infarct area. This concurred with a remarkable decrease in high mobility group box protein 1 (HMGB-1)/ nuclear factor kappa B (NF-κB) stimulation leading to less priming of NLRP3 inflammasome. Conclusion and implication: This preclinical evidence supporting verapamil as a safe adjunctive therapy in thrombolytic approaches, underlines TXNIP’s detrimental role in BBB disruption in metabolic distress.