Redox imbalance in the brain significantly contributes to ischemic stroke pathogenesis but antioxidant therapies have failed in clinical trials. Activation of endogenous 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 hypothesize that TXNIP inhibition attenuates redox imbalance and inflammation and provide protection against a clinically relevant model of embolic stroke. Male TXNIP-knockout (TKO), wild-type (WT) and WT mice treated with a pharmacological inhibitor of TXNIP, resveratrol (RES; 5mg/kg body weight) were subjected to embolic middle cerebral artery occlusion (eMCAO). Behavior outcomes were monitored using neurological deficits score and grip strength meter at 24 h after eMCAO. Expression of oxidative, inflammatory and apoptotic markers were analyzed by Western blot, immunohistochemistry and slot blot at 24h post-eMCAO. Our result showed that ischemic injury increases TXNIP in WT mice and that RES inhibits TXNIP expression and protects brain against ischemic damage. TKO and RES-treated mice exhibited 39.26% and 41.11% decrease in infarct size and improved neurological score and grip strength compared to WT mice after eMCAO. Furthermore, the levels of TRX, nitrotyrosine, NOD-like receptor protein (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α), and activations of caspase-1, caspase-3 and poly ADP ribose polymerase (PARP) were significantly (P<0.05) attenuated in TKO and RES-treated mice. The present study suggests that TXNIP is contributing to acute ischemic stroke through redox-imbalance and inflammasome activation, and 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.

These findings demonstrate that a single dose of C21 is neurovascular-protective and improves stroke outcome possibly through increasing neurotrophin activity, mitigating brain inflammation, and promoting antioxidant and pro-angiogenic effects.