HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-1669v1 57/4/889    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ali, T. K. Articles by El-Remessy, A. B. Search for Related Content PubMed PubMed Citation Articles by Ali, T. K. Articles by El-Remessy, A. B. Social Bookmarking                What's this?

Peroxynitrite Mediates Retinal Neurodegeneration by Inhibiting NGF Survival Signal in Experimental and Human Diabetes

1 Program in Clinical and Experimental Therapeutics, University of Georgia;
2 Department of Pharmacology and Toxicology;
3 Department of Ophthalmology, Medical College of Georgia;
4 VA Medical Center, Augusta, GA 30912

Objective: Recently we have shown diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show peroxynitrite impairs nerve growth factor (NGF) survival signal in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurodegeneration and NGF survival signal have not been elucidated.

Research Design and Methods: Expression of NGF and its receptors was examined in retinas from human and STZ-diabetic rats and retinal ganglion cells (RGC). Diabetic animals were treated with FeTPPs (IP, 15mg/kg/day), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDAassay, immunofluorescence and Slot-Blot analysis. Expression of NGF and its receptors was determined by ELISA, real-time PCR, immunoprecipitation and Western Blot analyses.

Results: Analyses of retinal neuronal death and NGF showed 9-fold and 2-fold increases, respectively, in diabetic retinas compared to controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75NTR receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its down-stream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 MAPK in RGC even in the presence of exogenous NGF. FeTPPs prevented tyrosine nitration, restored NGF survival signal and prevented neuronal death in vitro and in vivo.

Conclusion: Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75NTR expression.

Key Words: Peroxynitrite • apoptosis • tyrosine nitration • diabetic retinopathy • neuroprotection • NGF • TrkA • p75NTR

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?