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Suraporn Matragoon, Mohammed M. Al-Gayyar, Mohammed A. Abdelsaid, Bindu A. Pillai, Azza B. El-Remessy; Thioredoxin Interacting Protein Is a Novel Mediator of Retinal Inflammation and Neurotoxicity. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1006.
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© ARVO (1962-2015); The Authors (2016-present)
Upregulation of thioredoxin interacting protein (TXNIP), an endogenous inhibitor of thioredoxin, can compromise major cellular antioxidant and antiapoptotic defense as well as stimulate proinflammatory cytokines expression suggesting a potential role of TXNIP in mediating cell death. The aim of this study is to examine the casual role of TXNIP expression in mediating retinal neurotoxicity and to screen the neuroprotective actions of verapamil, a calcium channel blocker and an inhibitor of TXNIP expression.
Neurotoxicity was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in Sprague-Dawley rats, which received verapamil (10 mg Kg-1, po) or vehicle. Retinal neurotoxicity was examined by TUNEL assay and ganglion cell count. Expression of TXNIP, ASK-1, NFΚB, p38MAPK, JNK, cleaved PARP, caspase-3, nitrotyrosine and 4-HNE were examined by Western and slot-blot analysis. Release of TNF-α and IL-1β was examined by ELISA.
NMDA injection significantly enhanced TXNIP expression, decreased Trx activity resulting in significant increases in oxidative stress, glial activation and release of TNF-α and IL-1β. The enhanced TXNIP expression disrupted Trx/ASK-1 inhibitory complex leading to release of the ASK-1 and activation of the proapoptotic p38MAPK/JNK pathway as indicated by cleaved PARP and caspase-3 expression. Treatment with verapamil blocked these effects.
Elevated TXNIP expression can contribute to retinal neurotoxicity by three different mechanisms; inducing release of inflammatory mediators as TNF-α and IL-1β, altering antioxidant status and disrupting Trx-ASK-1 inhibitory complex leading to activation of p38MAPK/JNK apoptotic pathway. Targeting TXNIP expression is a potential therapeutic target for retinal neurodegenerative disease.
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