Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury

M. F. El-Azab, B. R.B. Baldowski, B. A. Mysona, A. Y. Shanab, I. N. Mohamed, M. A. Abdelsaid, S. Matragoon, Kathryn Elizabeth Bollinger, Alan B Saul, A. B. El-Remessy

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Background and Purpose: Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration. Experimental Approach: Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram. Key Results: NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1β that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1β and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice. Conclusion and Implications: Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)1299-1313
Number of pages15
JournalBritish Journal of Pharmacology
Volume171
Issue number5
DOIs
StatePublished - Mar 2014

Keywords

  • ERG
  • IL-1β
  • Müller cell
  • NMDA
  • TNF-α
  • TXNIP
  • acellular capillary
  • apoptosis
  • neurotoxicity
  • retina
  • vascular permeability

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    El-Azab, M. F., Baldowski, B. R. B., Mysona, B. A., Shanab, A. Y., Mohamed, I. N., Abdelsaid, M. A., Matragoon, S., Bollinger, K. E., Saul, A. B., & El-Remessy, A. B. (2014). Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury. British Journal of Pharmacology, 171(5), 1299-1313. https://doi.org/10.1111/bph.12535