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Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity
Author(s) -
AlGayyar Mohammed MH,
Abdelsaid Mohammed A,
Matragoon Suraporn,
Pillai Bindu A,
ElRemessy Azza B
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01336.x
Subject(s) - txnip , neurotoxicity , thioredoxin interacting protein , neuroprotection , p38 mitogen activated protein kinases , biology , pharmacology , mapk/erk pathway , oxidative stress , chemistry , microbiology and biotechnology , signal transduction , thioredoxin , biochemistry , toxicity , organic chemistry
BACKGROUND AND PURPOSE Up‐regulation of thioredoxin interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (Trx), compromises cellular antioxidant and anti‐apoptotic defences and stimulates pro‐inflammatory cytokines expression, implying a role for TXNIP in apoptosis. Here we have examined the causal role of TXNIP expression in mediating retinal neurotoxicity and assessed the neuroprotective actions of verapamil, a calcium channel blocker and an inhibitor of TXNIP expression. EXPERIMENTAL APPROACH Retinal neurotoxicity was induced by intravitreal injection of NMDA in Sprague–Dawley rats, which received verapamil (10 mg·kg −1 , p.o.) or vehicle. Neurotoxicity was examined by terminal dUTP nick‐end labelling assay and ganglion cell count. Expression of TXNIP, apoptosis signal‐regulating kinase 1 (ASK‐1), NF‐κB, p38 MAPK, JNK, cleaved poly‐ADP‐ribose polymerase (PARP), caspase‐3, nitrotyrosine and 4‐hydroxy‐nonenal were examined by Western and slot‐blot analysis. Release of TNF‐α and IL‐1β was examined by elisa . KEY RESULTS NMDA injection enhanced TXNIP expression, decreased Trx activity, causing increased oxidative stress, glial activation and release of TNF‐α and IL‐1β. Enhanced TXNIP expression disrupted Trx/ASK‐1 inhibitory complex leading to release of ASK‐1 and activation of the pro‐apoptotic p38 MAPK/JNK pathway, as indicated by cleaved PARP and caspase‐3 expression. Treatment with verapamil blocked these effects. CONCLUSION AND IMPLICATIONS Elevated TXNIP expression contributed to retinal neurotoxicity by three different mechanisms, inducing release of inflammatory mediators such as TNF‐α and IL‐1β, altering antioxidant status and disrupting the Trx‐ASK‐1 inhibitory complex leading to activation of the p38 MAPK/JNK apoptotic pathway. Targeting TXNIP expression is a potential therapeutic target for retinal neurodegenerative disease.