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A. B. El-Remessy, T. K. Ali, B. A. Pillai, S. Matragoon; Epicatechin Prevents Gliosis and Neuronal Death in Diabetes: Critical Role of MMP-7. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5375.
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We have previously shown positive correlation between peroxynitrite, neuronal death and accumulation of the proform of nerve growth factor (proNGF) in diabetic rat retinas. ProNGF is cleaved to the mature NGF by the extracellular protease MMP-7. The purpose of this study is to elucidate the role of tyrosine nitration in mediating diabetes-induced glial activation, proNGF accumulation and neuronal death and to evaluate the protective effects of the selective nitration inhibitor epicatechin.
Sprague-Dawley rats were rendered diabetic using streptozotosin and treated with epicatechin (100mg/kg/day, oral). Muller cells (rMC-1) were treated with high glucose (25 mM) or normal glucose (5mM). Neuronal cell death was determined by TUNEL assay in flat-mounted retinas. Nitrotyrosine was determined using Slot-Blot analysis. Expression of NGF and proNGF were determined by Western-Blot. MMP-7 activity was determined by FRET assay.
Diabetes/high glucose increased nitrotyrosine and decreased the expression and activity of MMP-7 which resulted in accumulation of proNGF in retinal Muller cells compared to controls. Diabetes induced the expression of NGF receptor p75NTR and neuronal cell death. Treatment of diabetic animals with epicatechin blocked tyrosine nitration, restored MMP-7 activity and NGF maturation and prevented neuronal cell death.
Diabetes-induced peroxynitrite formation activates glia, stimulates proNGF accumulation via inhibition of MMP-7 leading to retinal neurodegeneration. Normalizing peroxynitrite using epicatechin prevents accumulation of proNGF, restores NGF levels and reduces neurotoxicity in the diabetic retina. Thus, inhibiting tyrosine nitration may be effective therapeutic targets in early diabetic retinopathy.
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