Thioredoxin interacting protein is a novel mediator of retinal inflammation and neurotoxicity.

Abstract

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.

• Authors: Mohammed M H Al-Gayyar, Mohammed A Abdelsaid, Suraporn Matragoon, Bindu A Pillai, Azza B El-Remessy
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 164 Issue 1 Pg. 170-80 (Sep 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21434880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Carrier Proteins
• Caspase Inhibitors
• Cell Cycle Proteins
• Interleukin-1beta
• NF-kappa B
• Neuroprotective Agents
• Poly(ADP-ribose) Polymerase Inhibitors
• TXNIP protein, rat
• Tumor Necrosis Factor-alpha
• 3-nitrotyrosine
• Tyrosine
• Thioredoxins
• Verapamil
• Poly(ADP-ribose) Polymerases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP Kinase Kinase 4
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Carrier Proteins (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Caspase 3 (metabolism)
• Caspase Inhibitors
• Cell Cycle Proteins
• Eye Diseases (genetics, metabolism, pathology)
• Inflammation (genetics, metabolism, pathology)
• Interleukin-1beta (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 4 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors, metabolism)
• Male
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neuroglia (metabolism)
• Neuroprotective Agents (pharmacology)
• Oxidative Stress (drug effects)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Retina (drug effects, metabolism)
• Retinal Ganglion Cells (drug effects, metabolism)
• Thioredoxins (antagonists & inhibitors, metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)
• Tyrosine (analogs & derivatives, metabolism)
• Up-Regulation (genetics)
• Verapamil (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)