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Objective Increased levels of glutamate in vitreous and/or retinas of patients and animal models of diabetes are believed to contribute to the pathophysiology of neuronal loss in diabetic retinopathy (DP).This study is to explore possible association of morphological changes with the expression of GLAST, a prominent glutamate-aspartate transporter, and if glial cell line-derived neurotrophic factor (GDNF) administration could ameliorate the changed retinal morphology and cell apoptosis.Methods All experiments were conducted in 4-week streptozotocin (STZ)-diabetic rats and age-matched normal SD rats.GDNF was injected into the vitreous space of one eye chosen at random with a total of three times beginning 2 weeks after STZ injection.Changes in GLAST protein expression levels were determined by Western blot analysis.Pathophysiological impairments of retinas were evaluated by in situ end labeling of DNA terminal dUTP nick end labeling (TUNEL) analysis and HE staining.Results Western blot analysis showed that GLAST levels were decreased by 61.66% in STZ-treated rat retinas, compared to control (P<0.05).Morphometric analysis of STZ-treated rat retinas revealed that the inner plexiform layer (IPL) was significantly reduced in thickness (P<0.01) and more TUNEL-positive cells were found (P<0.05) in the outer nuclear layer (ONL).GDNF administration remarkably increased GLAST levels by 124.90%, as compared to the vehicle-treated group (P<0.01).Additionally, the number of TUNEL-positive cells in the ONL became lower (P<0.05) and the IPL was rather well preserved in the GDNF-treated group.Furthermore, intraocular injection of short interfering RNAs (siRNAs) directed against GLAST antagonized the upregulation of GLAST by GDNF.Co-administration of GLAST siRNA resulted in a significant increase in number of TUNEL-positive cells in the ONL and thinner IPL.Conclusion Intraocular administration of GDNF effectively ameliorates retinal damages in STZ-induced diabetic rats, which could be in part due to GDNF-induced upregulation of GLAST.