TY - JOUR
T1 - Thioredoxin-Interacting Protein
T2 - a Novel Target for Neuroprotection in Experimental Thromboembolic Stroke in Mice
AU - Ishrat, Tauheed
AU - Mohamed, Islam N.
AU - Pillai, Bindu
AU - Soliman, Sahar
AU - Fouda, Abdelrahman Y.
AU - Ergul, Adviye
AU - El-Remessy, Azza B.
AU - Fagan, Susan C.
N1 - Funding Information:
The authors are grateful to Dr. JA Lusis for providing TKO mice. This study was supported by the Veterans Affairs Merit Review (SCF, BX000891, NIH – R01 (SCF, NS063965), and NIH – R01 (ABE, EY022408). Authors would like to thank Ms Colby Polonsky for her assistance with Cover page image.
Funding Information:
SCF is a consultant for and has received funding from Pfizer.
Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2015/4
Y1 - 2015/4
N2 - 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.
AB - 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.
KW - Antioxidant
KW - Embolic stroke
KW - Inflammasome
KW - Oxidative stress
KW - Resveratrol
KW - Thioredoxin-interacting protein
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UR - http://www.scopus.com/inward/citedby.url?scp=84939779243&partnerID=8YFLogxK
U2 - 10.1007/s12035-014-8766-x
DO - 10.1007/s12035-014-8766-x
M3 - Article
C2 - 24939693
AN - SCOPUS:84939779243
SN - 0893-7648
VL - 51
SP - 766
EP - 778
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 2
ER -