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Thioredoxin-Interacting Protein: a Novel Target for Neuroprotection in Experimental Thromboembolic Stroke in Mice

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An Erratum to this article was published on 11 December 2014

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.

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Abbreviations

PARP:

Poly-ADP-ribose polymerase

ROD:

Relative optical density

TRX:

Thioredoxin

TXNIP:

Thioredoxin-interacting protein

eMCAO:

Embolic middle cerebral artery occlusion

NLRP3:

NOD-like receptor pyrin domain containing-3

IL-1β:

Interleukin-1β

TNF-α:

Tumor necrosis factor-α

RES:

Resveratrol

ROS:

Reactive oxygen species

NT:

Nitrotyrosine

WT:

Wild type

TKO:

TXNIP-knockout

TTC:

2, 3, 5-Triphenyltetrazolium chloride

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Acknowledgments

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.

Conflict of Interest

SCF is a consultant for and has received funding from Pfizer.

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Authors and Affiliations

  1. Charlie Norwood VA Medical Center, Augusta, GA, USA

    Tauheed Ishrat, Islam N. Mohamed, Bindu Pillai, Sahar Soliman, Abdelrahman Y. Fouda, Adviye Ergul, Azza B. El-Remessy & Susan C. Fagan

  2. Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, HM 1212; 1120 15th St., Athens, GA, 30912, USA

    Tauheed Ishrat, Islam N. Mohamed, Bindu Pillai, Sahar Soliman, Abdelrahman Y. Fouda, Adviye Ergul, Azza B. El-Remessy & Susan C. Fagan

  3. Department of Physiology, Georgia Regents University, Augusta, GA, USA

    Adviye Ergul

  4. Department of Neurology, Georgia Regents University, Augusta, GA, USA

    Susan C. Fagan

  5. Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA

    Azza B. El-Remessy

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  1. Tauheed Ishrat
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Ishrat, T., Mohamed, I.N., Pillai, B. et al. Thioredoxin-Interacting Protein: a Novel Target for Neuroprotection in Experimental Thromboembolic Stroke in Mice. Mol Neurobiol 51, 766–778 (2015). https://doi.org/10.1007/s12035-014-8766-x

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