title: Thioredoxin-interacting protein: a novel target for neuroprotection in experimental thromboembolic stroke in mice.
abstract: 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.
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA, USA, tauheedarshi@gmail.com.
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Islam N
authors.initials: IN
authors.lastname: Mohamed
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.forename: Sahar
authors.initials: S
authors.lastname: Soliman
authors.forename: Abdelrahman Y
authors.initials: AY
authors.lastname: Fouda
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control*; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013923:Thromboembolism / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D002352:Carrier Proteins; D013267:Stilbenes; C445672:Txnip protein, mouse; D013879:Thioredoxins; D000077185:Resveratrol