Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma

Abstract

We investigated the neuroprotective effect of thioredoxin 1 (Trx1) and thioredoxin 2 (Trx2) which play critical roles in the regulation of oxidative stress on retinal ganglion cells (RGCs) in a rat glaucoma model. Expression of Trx1 and Trx2 and Trx-interacting protein (Txnip) was observed in the RGC layer (GCL), nerve fiber layer and inner nuclear layer. Txnip-, Trx1-and Trx2-expressing cells in the GCL were primarily colocalized with RGCs. The increased Txnip protein level was observed 2 and 5 weeks after glaucoma induction. Trx1 level decreased 2 weeks after glaucoma induction and more prominently after 5 weeks. No change in Trx2 levels was detected. The effects of Trx1 and Trx2 overexpression on RGC survival were evaluated 5 weeks after glaucoma induction. In nontransfected and EGFP-transfected (used as a negative control) retinas, RGC loss was approximately 27% compared with control. The loss of RGCs in Trx1-and Trx2-transfected retinas was approximately 15 and 17%, respectively. Thus, Trx1 and Trx2 preserved 45 and 37% of cells, respectively that were destined to die in glaucomatous retinas. The results of this study provide evidence for the involvement of oxidative stress in RGC degeneration in experimental glaucoma and point to potential strategies to reduce its impact.

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

“…In support, several studies demonstrated that restoring Trx activity can prevent RGC death and apoptosis in aging liver cells or cardiomyocytes. 11,[33][34][35] However, our study is the first one to demonstrate a causal role of peroxynitrite in increasing TXNIP expression, altering thioredoxin system and activating ASK-1 proapoptotic pathway leading to RGC death in NMDA model.…”

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

“…[29][30][31] In resting cells, ASK1 constantly forms an inactive complex with thioredoxin, whereas upon stimulation, ASK1 is dissociated from thioredoxin and activated by conformational changes and covalent modifications.…”

“…31,32 On the other hand, PB1, a novel phosphineborane complex, promotes RGC protection through the induction of BDNF and activation of the extracellular signal-regulated kinases 1/2, but not ASK1, signaling. 33 The identification of small-molecule compounds that mimic some of the beneficial effects of trophic factors is of clinical interest.…”

Reduced-serum vitamin C and increased uric acid levels in normal-tension glaucoma

“…Feilchenfeld et al reported that increased nitrotyrosine (a footprint for oxidative injury) is present in blood vessels and astrocytes in the pre-laminar optic nerve head in human primary open-angle glaucoma than controls [5]. Current evidence points to the association between oxidative stress and ganglion cell death without IOP elevation, which may be the cause of NTG in vivo and in vitro [11][12][13][14][15]. Harada et al reported that in glutamate transporter knock-out mice, decreased glutathione, a major cellular antioxidant, may cause retinal ganglion cell apoptosis without IOP elevation [15].…”