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M. M. H. Al-Gayyar, M. A. Abdelsaid, S. Matragoon, B. A. Pillai, A. B. El-Remessy; Neuro and Vascular Protective Effect of FeTPPs in NMDA-Model: Similarity to Diabetes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3693.
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We have previously shown neuro and vascular protective effects of decomposing peroxynitrite using FeTPPs in models of diabetic and oxygen-induced retinopathy. Intravitreal-injection of N-methyl-D-aspartic acid (NMDA) is an established model to study acute retinal ganglion cell degeneration. This study will elucidate the role of peroxynitrite in activating the apoptotic ASK-1 pathway and alterating thioredoxin interacting protein (TXNIP) and thioredoxin (Trx), a major cellular antioxidant and anti-apoptotic protein. Furthermore, we will investigate the neuro/vascular protective effects of FeTPPs on glial activation and capillary degeneration in NMDA model.
SD Rats received intravitreal-injection of either NMDA, NMDA and FeTPPs or the control N-methyl-L-aspartic acid (NMLA). For short term (1 day), retinal neurotoxicity was examined by TUNEL assay and ganglion cell (GC) count. Glial activation and peroxynitrite were assessed by immunohistochemistry. Expression of TXNIP, pp-38 and PARP and interaction of Trx/TXNIP and Trx/ASK-1 were analysed by Western-Blot. For long term effects (7days), acellular capillaries and pericytes were counted in retinal trypsine digest.
Intravitreal-injection of NMDA caused significant increases in neuronal cell death and reduced GC count compared with NMLA. This effects was associated with enhanced nitrotyrosine and TXNIP expression which disrupt Trx-ASK-1 inhibitory complex leading to release of ASK-1. Activation of ASK-1 proapoptotic pathway was evident by increases in p-p38 and PARP expression in NMDA-injected retinas. NMDA causes glial activation and capillary degeneration as indicated by prominent GFAP, 1.7-fold increase in acellular capillaries and 25 % reduction in number of preicytes. Treatment with FeTPPs blocked these effects in NMDA-injected rats.
NMDA-induced retinal neuro/vascular injury is mediated in part by increasing peroxynitrite and reducing the antioxidant defense which in turn activates ASK-1 apoptotic pathway. In addition to neurotoxicity, NMDA-model can be useful tool to study glial activation and capillary degeneration, hall marks of diabetic retinopathy in much shorter time.
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