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Proceedings Paper

Neuroprotection in rabbit retina with N-acetyl-aspartylglutamate and 2-phosphonyl-methyl pentanedioic acid
Author(s): Henry D. Hacker; Debra L. Yourick; Michael K. Koenig; Barbara S. Slusher; James L. Meyerhoff
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Paper Abstract

Retinal tissue is subject to ischemia from diabetic retinopathy and other conditions that affect the retinal vasculature such as lupus erythematosus and temporal arteritis. There is evidence in animal models of reversible ischemia that a therapeutic window exists during early recovery when agents that reduce glutamate activity at its receptor sites can rescue neurons from injury. To model ischemia, we used sodium cyanide (NaCN), to inhibit oxidative metabolism, and 2-deoxyglucose (2-DG) to inhibit glycolysis. Dissociated rabbit retina cells were studied to evaluate the potential neuroprotective effects of N-acetyl-aspartyl-glutamate (MAAG), which competes with glutamate as a low-potency agonist at the NMDA receptor complex. N-acetylated α-linked acidic dipeptidase (NAALADase; the NAAG-hydrolyzing enzyme) is responsible for the hydrolysis of NAAG into glutamate, a neurotransmitter and potent excitotoxin, and N-acetylaspartate. 2-Phosphonyl-methyl pentanedioic acid (PMPA) and β-linked NAAG (β-NAAG), inhibitors of NAALADase, were also tested, since inhibition of NAALADase could reduce synaptic glutamate and increase the concentration of NAAG. We found that metabolic inhibition with NaCN/2-DG for 1 hour caused 50% toxicity as assessed with the MTT assay. Co-treatment with NAAG resulted in dose-dependent protection of up to 55% (p<0.005). When the non-hydrolyzable, NAALADase inhibitor β-NAAG was employed dose-dependent protection of up to 37% was observed (p<0.001). PMPA also showed 48% protection (p<.05-.001) against these insults. These data suggest that NAAG may antagonize the effect of glutamate at the NMDA receptor complex in retina. Inhibition of NAALADase by PMPA and β-NAAG may increase the activity of endogenous NAAG.

Paper Details

Date Published: 18 June 1999
PDF: 8 pages
Proc. SPIE 3591, Ophthalmic Technologies IX, (18 June 1999); doi: 10.1117/12.350612
Show Author Affiliations
Henry D. Hacker, Darnall Army Community Hospital (United States)
Debra L. Yourick, Walter Reed Army Institute of Research (United States)
Michael K. Koenig, Walter Reed Army Institute of Research (United States)
Barbara S. Slusher, Guilford Pharmaceuticals (United States)
James L. Meyerhoff, Walter Reed Army Institute of Research (United States)

Published in SPIE Proceedings Vol. 3591:
Ophthalmic Technologies IX
Bruce E. Stuck; Pascal O. Rol; Michael Belkin; Karen Margaret Joos; Fabrice Manns; Bruce E. Stuck; Michael Belkin, Editor(s)

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