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 provides 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; 5 mg/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 was analyzed by Western blot, immunohistochemistry, and slot blot at 24 h post-eMCAO. Our result showed that ischemic injury increases TXNIP in WT mice and that RES inhibits TXNIP expression and protects the brain against ischemic damage. TKO and RES-treated mice exhibited a 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.