Abstract WMP82: Inhibition of Thioredoxin Interacting Protein Attenuates Tissue Plasminogen Activator Induced Brain Damage Under Acute Hyperglycemia in Murine Stroke Model

Abstract

Background and Hypothesis: Acute hyperglycemia (AHG) worsens stroke outcome and increases the risk of intracerebral hemorrhage after tissue plasminogen activator (tPA) treatment, independent of preexisting diabetes. We have previously reported that genetic deletion of thioredoxin interacting protein exerts neuroprotection after experimental stroke. Here we tested the hypothesis that pharmacological inhibition of TXNIP, with verapamil protects against tPA-induced brain damage under AHG in a mouse model of focal cerebral ischemia. Methods: Transient focal cerebral ischemia was induced by a 60 min middle cerebral artery occlusion (MCAO) followed by 23 h reperfusion in mice. AHG was induced by administration of 20% glucose (ip), 15 minutes before MCAO. Verapamil (0.015 mg/kg, iv) and tPA (iv), or saline was administered at 1 h post-occlusion. After 24 h of I/R, mice were tested for neurobehavioral outcome and were evaluated for infarct size and expression inflammatory mediators, and blood brain barrier markers. Results: AHG aggravated brain edema, blood brain disruption and neuroinflammation. Treatment with verapamil significantly reduced in the infarct size (41%, p<0.05), hemorrhage (36%) and edema (36%, p<0.05) compared to saline treated controls. Furthermore, verapamil significantly inhibited the TXNIP mediated activation of NLRP3-inflammsome and ameliorated blood brain barrier leakage (Table 1). Conclusion: Taken together, these data indicate that inhibition of TXNIP with verapamil may have therapeutic implications on ischemic stroke in the acute hyperglycemic condition.