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Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes.
Am J Pathol. 2010 Sep; 177(3):1187-97.AJ

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.

Authors+Show Affiliations

Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20651233

Citation

Al-Gayyar, Mohammed M H., et al. "Neurovascular Protective Effect of FeTPPs in N-methyl-D-aspartate Model: Similarities to Diabetes." The American Journal of Pathology, vol. 177, no. 3, 2010, pp. 1187-97.
Al-Gayyar MM, Abdelsaid MA, Matragoon S, et al. Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes. Am J Pathol. 2010;177(3):1187-97.
Al-Gayyar, M. M., Abdelsaid, M. A., Matragoon, S., Pillai, B. A., & El-Remessy, A. B. (2010). Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes. The American Journal of Pathology, 177(3), 1187-97. https://doi.org/10.2353/ajpath.2010.091289
Al-Gayyar MM, et al. Neurovascular Protective Effect of FeTPPs in N-methyl-D-aspartate Model: Similarities to Diabetes. Am J Pathol. 2010;177(3):1187-97. PubMed PMID: 20651233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes. AU - Al-Gayyar,Mohammed M H, AU - Abdelsaid,Mohammed A, AU - Matragoon,Suraporn, AU - Pillai,Bindu A, AU - El-Remessy,Azza B, Y1 - 2010/07/22/ PY - 2010/7/24/entrez PY - 2010/7/24/pubmed PY - 2010/12/14/medline SP - 1187 EP - 97 JF - The American journal of pathology JO - Am J Pathol VL - 177 IS - 3 N2 - 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. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/20651233/Neurovascular_protective_effect_of_FeTPPs_in_N_methyl_D_aspartate_model:_similarities_to_diabetes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9440(10)60174-5 DB - PRIME DP - Unbound Medicine ER -