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

作者：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; El Remessy A B^*

来源：British Journal of Pharmacology, 2014, 171(5): 1299-1313.

DOI：10.1111/bph.12535

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

Background and PurposeRetinal 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 ApproachNeurotoxicity 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 ResultsNMDA 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- and IL-1 that co-localized with Muller 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-1 and TNF- in primary WT but not TKO Muller 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 ImplicationsTargeting 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.

• 出版日期2014-3