Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes
Authors: Azza B El-Remessy
Mohammed A Abdelsaid
Suraporn Matragoon
Mohammed M H Al-Gayyar
Bindu A Pillai
Journal: American Journal Of Pathology (2010)
Discipline: CLINICAL MEDICINE
Keywords: peroxynitrite; retinal ganglion cell; thioredoxin system; glial activation; capillary degeneration
Affiliations: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA.

Abstract:  We have previously shown a causal role of peroxynitrite in mediating retinal ganglion cell (RGC) death in diabetic and neurotoxicity models. In the present study, the role of peroxynitrite in altering the antioxidant and antiapoptotic thioredoxin (Trx) system will be investigated as well as the subsequent effects on glial activation and capillary degeneration. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-d-aspartate (NMDA) in rats, which also received the peroxynitrite decomposition catalyst FeTPPs. RGC loss was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and GC count. Glial activation and nitrotyrosine were assessed by immunohistochemistry. Acellular capillaries and pericytes were counted in retinal trypsin digest. NMDA-induced peroxynitrite formation caused RGC loss, which was associated with enhanced expression of Trx and its endogenous inhibitor thioredoxin interacting protein. The results also showed enhanced thioredoxin interacting protein/Trx binding and disruption of the Trx/apoptosis signal-regulating kinase 1 "inhibitory complex," leading to release of apoptosis signal-regulating kinase 1 and activation of the apoptotic pathway, as evidenced by p38 MAPK and poly-ADP-ribose polymerase activation. Furthermore, NMDA caused glial activation and compromised retinal vasculature, as indicated by acellular-capillary formation and pericyte loss. Treatment with FeTPPs blocked these effects. In conclusion, NMDA-induced retinal neuro/vascular injury is mediated by peroxynitrite-altered Trx antioxidant defense, which in turn activates the apoptosis signal-regulating kinase-1 apoptotic pathway. In addition to acute RGC death, an NMDA model can be a useful tool to study glial activation and capillary degeneration in retinal neurodegenerative disorders, including diabetic retinopathy. 

Retracted: No

PubPeer comments:
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 After slapping on a (hard to find) Note of Concern, the American Journal of Pathology appears to have completely forgotten about the concerns. So here are the concerns again, this time with illustrations. Figure 1C * Red boxes: The 2nd and 4th panel appear to show an overlap.  Figures 2 and 4: * Aqua boxes: NMDA+FeTPPs in Figure 2A appears to show an overlap with NMLA_FeTPPs in Figure 4D  Despite the fact that the University concluded that misconduct had occurred, the journal never retracted the paper. The paper has been cited 33 times, according to Scopus, and at least 8 of these citations were after the Note of Concern had been issued. Could the journal please take a look again at this paper and decide if they have a bit more courage this time to retract it? ,