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Deletion of thioredoxin‐interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury
Author(s) -
ElAzab 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,
ElRemessy A B
Publication year - 2014
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/bph.12535
Subject(s) - neurodegeneration , retinal degeneration , biology , txnip , retinal ganglion cell , retinal , excitotoxicity , retinal regeneration , microbiology and biotechnology , retina , pathology , programmed cell death , endocrinology , neuroscience , medicine , apoptosis , biochemistry , thioredoxin , oxidative stress , disease
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 M üller 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.