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Minocycline Reduces Proinflammatory Cytokine Expression, Microglial Activation, and Caspase-3 Activation in a Rodent Model of Diabetic Retinopathy

¹ Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
² Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania
³ Department of Neurology and Neuroscience, University of Medicine and Dentistry in New Jersey, New Jersey Medical School, Newark, New Jersey

Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1ß and tumor necrosis factor-, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.

Abbreviations: AMC, 7-amino-4-methyl coumarin; CNS, central nervous system; COX-2, cyclo-oxygenase-2; DAPI, 4',6-diamidino-2-phenylindole; IL, interleukin; LDH, lactate dehydrogenase; MEM, minimum essential medium; MMP, matrix metalloproteinases; NCS, newborn calf serum; ROS, reactive oxygen species; STZ, streptozotocin; TNF-, tumor necrosis factor-; TUNEL, transferase-mediated dUTP nick-end labeling; VEGF, vascular endothelial growth factor

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