title: Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: El-Azab
authors.forename: B R B
authors.initials: BR
authors.lastname: Baldowski
authors.forename: B A
authors.initials: BA
authors.lastname: Mysona
authors.forename: A Y
authors.initials: AY
authors.lastname: Shanab
authors.forename: I N
authors.initials: IN
authors.lastname: Mohamed
authors.forename: M A
authors.initials: MA
authors.lastname: Abdelsaid
authors.forename: S
authors.initials: S
authors.lastname: Matragoon
authors.forename: K E
authors.initials: KE
authors.lastname: Bollinger
authors.forename: A
authors.initials: A
authors.lastname: Saul
authors.forename: A B
authors.initials: AB
authors.lastname: El-Remessy
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005902:Glaucoma, Open-Angle / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016202:N-Methylaspartate; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000517:prevention & control; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D057772:Vascular System Injuries / Q000517:prevention & control
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; C445672:Txnip protein, mouse; C002744:3-nitrotyrosine; D014443:Tyrosine; D013879:Thioredoxins; D016202:N-Methylaspartate; D013880:Thioredoxin-Disulfide Reductase
keywords: ERG; IL-1β; Müller cell; NMDA; TNF-α; TXNIP; acellular capillary; apoptosis; neurotoxicity; retina; vascular permeability