Abstract T P204: Thioredoxin Interacting Protein: A Novel Target for Neuroprotection in Experimental Thromboembolic Stroke in Mice

Abstract

Background & Objective: Redox imbalance in the brain significantly contributes to ischemic stroke pathogenesis but antioxidant therapies have failed in clinical trials. Activation of endogenous antioxidant defense mechanisms may provide better protection against stroke-induced oxidative injury. TXNIP (thioredoxin-interacting protein) is an endogenous inhibitor of thioredoxin (TRX), a key antioxidant system. We tested the hypothesis that inhibition of TXNIP is neuroprotective in a clinically relevant model of embolic stroke. Methods: We determined the contribution of TXNIP inhibition to neuronal injury and functional outcome after embolic middle cerebral artery occlusion (eMCAO) using male TXNIP-knockout (TKO), wild-type (WT) and WT mice treated with a pharmacological inhibitor of TXNIP, resveratrol (RES; 5mg/kg body weight). Results: TKO and RES-treated mice exhibited 45.2% and 52.4% decrease in infarct size and improved neurological score and grip strength compared to WT mice after eMCAO. Moreover, the levels of nitrotyrosine, a marker of oxidative damage increased significantly after eMCAO, indicating oxidative brain injury. TXNIP inhibition reduced oxidative marker generation. Furthermore, TXNIP was involved in ischemic brain damage, as less TXNIP expression was found in the RES-treated mice following eMCAO. Conclusions: The present study suggests that unregulated TXNIP is contributes to acute ischemic stroke, and that inhibition of TXNIP may provide a new target for therapeutic interventions. This study also affirms the importance of the antioxidant effect of RES on the TRX/TXNIP system. Table 1 . Summary of experimental stroke data presented as mean ±SE. # p<0.05 * p<0.05 vs. respective control.