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Mairaj Siddiquei, Mohd Nawaz, Ahmed Abu El-Asrar; High-mobility group box-1 induces decreased brain-derived neurotrophic factor-mediated neuroprotection in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3239.
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To test the hypothesis that brain-derived neurotrophic factor (BDNF)-mediated neuroprotection is reduced by high-mobility group box-1 (HMGB1) in the diabetic retina.
Paired vitreous and serum samples from 46 PDR and 34 nondiabetic patients were assayed for BDNF, HMGB1, soluble receptor for advanced glycation end products (sRAGE), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1) and thiobarbituric acid reactive substances (TBARS). In addition, we examined retinas of diabetic and HMGB1 intravitreally injected rats for the expression of BDNF, HMGB1, synaptophysin, TBARS and cleaved caspase-3. Retinas were dissected out, snap frozen and stored at -700C until analysis was done. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) were used.
BDNF was not detected in vitreous samples. BDNF levels were significantly lower in serum samples from patients with PDR compared with nondiabetic patients (p=0.015), whereas HMGB1, sRAGE, sICAM-1 and TBARS levels were significantly higher in PDR serum samples (p<0.001; p=0.008; p=0.019; p=0.011, respectively). MCP-1 levels did not differ significantly between patients with PDR and nondiabetic patients (p=0.836). There was a significant inverse correlation between serum levels of BDNF and HMGB1 (r=0.342; p=0.049). Diabetes and intravitreal administration of HMGB1 induced significant upregulation of the expression of HMGB1, TBARS and cleaved caspase-3, whereas the expression of BDNF and synaptophysin was significantly downregulated in rat retinas.
Our data suggest that diabetes-induced increased oxidative stress, down-regulation of BDNF and synaptophysin and upregulation of cleaved caspase-3 were also induced by HMGB1. Collectively, our present data suggest that blocking HMGB1 signaling pathways might be a novel therapeutic strategy for neuronal dysfunction in vision-threatening diabetic retinopathy.
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