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Xinyuan Zhang, Mark C Gillies, Macular Research Group; Glucocorticoid Inhibits Neuronal Apoptosis and Protects Blood Retinal Barrier in Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4912.
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Diabetic macular edema (DME), a serious eye complication caused by abnormal glucose metabolism, is one of the major causes of blindness. In contrast with anti-VEGF therapy on DME, glucocorticoids may also exert neuroprotective effects. How glucocorticoids protect retinal neurons as well as the protect effects on blood retinal barrier (BRB) are unknown. The aims of the study are to investigate the anti-apoptotic actions of glucocorticoids on diabetic retinal neurons, characterize the signaling pathways involved and to evaluate the protective effects on BRB.
The regulation of gene expression of the four p38 mitogen-activated protein kinase (MAPK) isoforms (α, β, δ and γ), the glucocorticoid receptor (GR), the occluding and the Occludin as well as ZO-1 in the retinas was evaluated using quantitative RT-PCR, Western blot and immunohistochemistry. Phosphorylation of all isoforms p38MAPK (Thr180/Tyr182) and GR (S-211), the expression of ZO-1 and Occludin at protein level was further evaluated. Apoptosis was confirmed by immunolocalization of active CASPASE-3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP) following intravitreal injection of triamcinolone acetonide (IVTA), in an early diabetic rat model (26 days after induction of diabetes).
IVTA significantly down-regulated mRNA expression of Caspase 3 but up-regulated ZO-1 and Occludin. Activation of CASPASE-3, the subsequent cleavage of PARP-1 and phosphorylation of p38MAPK induced by diabetes were attenuated by IVTA treatment, concomitantly with activation by phosphorylation of the glucocorticoid receptor (GR S-211) and ZO-1.
Glucocorticoids activates the GR and exerts neural protective effects on retinal neurons. Inhibition of the p38MAPK pathway and activation of GR play a critical anti-apoptotic role in retinal neurons of diabetes following IVTA treatment. Glucocorticoid protects BRB throught increasing the expression of tight junction proteins.
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