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

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

doi:10.1007/s12035-020-01893-7

Cited by 39 publications

(34 citation statements)

References 74 publications

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“…Consistent with earlier findings (Ismael, Nasoohi, Yoo, Ahmed & Ishrat, 2020), we discovered that IV-tPA, even when administered early, well within its golden time; may exacerbate BBB breakdown in hyperglycemic reperfusion. Gross screening of coronal sections obtained from hyperglycemic brains showed more ipsilateral hemorrhages in those treated with tPA (Fig 5.…”

Section: Adjunctive Therapy With Verapamil Blocks Tpa-induced Cerebrosupporting

confidence: 91%

“…While suggested as a therapeutic target in endothelial damage induced by metabolic stress (Bedarida et al, 2018;Ren et al, 2018), TXNIP has a critical role in accelerating the degradation of glucose trasporter-1 (GLUT-1) and deterring glucose availability to brain cells (Waldhart et al, 2017). Most recently we found that intravenous tPA is associated with escalated TXNIP upregulation in stroked animals with acute hyperglycemia (Ismael, Nasoohi, Yoo, Ahmed & Ishrat, 2020), which may reasonably link tPA therapy to worse outcomes in hyperglycemic stroke (Ishrat et al, 2015). Upon stimulation by oxidative stress or high glucose, TXNIP restrains thioredoxin's antioxidant activity exacerbating propagation of reactive oxygen species (ROS) to accelerate reperfusion injury.…”

Section: Introductionmentioning

confidence: 98%

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Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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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.

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Section: Adjunctive Therapy With Verapamil Blocks Tpa-induced Cerebrosupporting

confidence: 91%

Section: Introductionmentioning

confidence: 98%

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

Self Cite

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“…On a parallel level, glucose injection exacerbated postischemic inflammation, apoptosis, and brain injury. A growing body of evidence has suggested that there is a proinflammatory effect of hyperglycemia, even in the CNS [2,[5][6][7][8][9][10]. Here, the inhibition of brain TNF-α production implies that the neuroprotective effects of insulin against cerebral ischemic injury may be secondary to its hypoglycemic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Despite their protective and regenerative potential, overwhelming hyperglycemia and neuroinflammation have been implicated in the pathogenesis of stroke. Rodent studies have also revealed the crosstalk among tPA, hyperglycemia, and neuroinflammation in cerebral ischemic brain injury, and the existing therapeutic benefits by means of targeting hyperglycemia and neuroinflammation [6][7][8][9][10]. These phenomena underscore the importance of exploring the underlying mechanisms of stroke-accompanied hyperglycemia and neuroinflammation, as well as highlighting their therapeutic potential towards combating stroke disease and related complications.…”

Section: Introductionmentioning

confidence: 96%

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke

Lin

Wang

Chang

et al. 2020

Cells

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Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective β-adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated—while glucose augmented—postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-α signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke.

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“…Once activated, caspase-1 triggers the conversion of pro-interleukin (IL)-1β or pro-IL-18 to mature IL-1β or IL-18, thereby inducing inflammation. 10,11 Moreover, active caspase-1 plays an important role in cleaving gasdermin D (GSDMD), a member of the gasdermin family, to induce pyroptosis. 12,13 Numerous studies have shown that pyroptosis is critical for multiple diseases, such as cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

Che

Yang

et al. 2020

FASEB j.

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Diabetes mellitus (DM) patients are at a higher risk of developing brain injury characterized by neuronal death. Melatonin, a hormone produced by the pineal gland, exerts neuroprotective effects against brain damage. However, the effect of melatonin on diabetes‐induced brain injury has not been elucidated. This study was to evaluate the role of melatonin against neuronal death in DM and to elucidate the underlying mechanisms. Herein, we found that melatonin administration significantly alleviated the neuronal death in both streptozotocin (STZ)‐induced diabetic mice and high glucose (HG)‐treated neuronal cells. Melatonin inhibited neuronal pyroptosis and excessive autophagy, as evidenced by decreased levels of NLRP3, cleaved caspase‐1, GSDMD‐N, IL‐1β, LC3, Beclin1, and ATG12 both in vivo and in vitro. MicroRNA‐214‐3p (miR‐214‐3p) was decreased in DM mice and HG‐treated cells, and such a downregulation was corrected by melatonin, which was accompanied by repression of caspase‐1 and ATG12. Furthermore, downregulation of miR‐214‐3p abrogated the anti‐pyroptotic and anti‐autophagic actions of melatonin in vitro. Our results indicate that melatonin exhibits a neuroprotective effect by inhibiting neuronal pyroptosis and excessive autophagy through modulating the miR‐214‐3p/caspase‐1 and miR‐214‐3p/ATG12 axes, respectively, and it might be a potential agent for the treatment of brain damage in the setting of DM.

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

Cited by 39 publications

References 74 publications

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

Effects of β-Adrenergic Blockade on Metabolic and Inflammatory Responses in a Rat Model of Ischemic Stroke

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

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