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C Beadle, T Ruzich, EA Ellis, DW Player, PE Spoerri, S Caballero, KM Wozniak, BS Slusher, MB Grant; NAALADase (GCP II) Inhibition Attenuates Basement Membrane Thickening And Pericyte Loss In Type 1 Diabetic BB/Wor Rat Retinopathy . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1349.
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Purpose:Early retinal changes associated with diabetic retinopathy include retinal capillary basement membrane (BM) thickening and pericyte degeneration. Both of these changes lead to a loss in the integrity of the capillary wall resulting in leakage into the retina and vitreous. The production of excitotoxic glutamate by neurons and glial cells is thought to contribute to the development of these early retinal changes. One source of glutamate results from cleavage of the neuropeptide N-acetyl-aspartyl-glutamate by glutamate carboxypeptidase II (GCPII; also known as NAALADase) and yields N-acetyl-aspartate and glutamate. Our purpose is to determine if the inhibition of GCP II will effect the development of diabetic retinopathy. Methods:In this study we used the spontaneously diabetic BB/Wor rat that develops pathological changes characteristic of human type 1 (insulin dependent) diabetes. BB/Wor rats were treated daily with the GCP II inhibitor GPI 5693 (10 or 30 mg/kg p.o) beginning at the onset of diabetes. Results:GCP II inhibition had no effect on blood glucose or body weight. The six month high dose (30 mg/kg) treatment with GPI 5693 resulted in a 29.2% reduction in BM thickness (vehicle = 96.0 13.32 nm and GPI 5693 = 68.0 6.06 nm; p<0.05), and was accompanied by a 33.0% reduction of endothelial cell to pericyte ratios (vehicle = 3.0 0.1 and GPI 5693 = 2.0 0.9; p<0.001). Treatment with the low dose of GCP II inhibitor (10 mg/kg) resulted in a 16.7% reduction of the same cell ratio (GPI 5693 = 2.5 0.5, p<0.05). Conclusion:These data suggest that GCP II inhibition may be a useful pharmacotherapy to prevent or reduce the development of diabetic retinopathy.
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