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S. Mohr, J. Vincent; Minocycline Prevents Caspase–1 Activation, Interleukin–1ß Production, and the Formation of Acellular Capillaries in the Retina of Diabetic Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4706.
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Purpose: Caspase–1 is responsible for the production of the pro–inflammatory cytokine interleukin–1ß, which is known to induce vascular permeability, upregulation of adhesion molecules, and cell death among several other functions. We have previously shown that hyperglycemia induces the activation of caspase–1 in the retina of diabetic mice and humans. Therefore, this study is focused on the effect of minocycline, a second–generation tetracycline and proposed caspase–1 inhibitor, on hyperglycemia–induced interleukin–1ß production, caspase–1 activation, subsequent activation of downstream caspases, and retinal pathology in retinas of diabetic mice. Methods: Mice made diabetic using streptozotocin were injected intraperitoneal with minocycline (5mg/kg body weight) 3 or 7 times a week for 2 months or 3 times a week for 6 months. Caspase activities were measured by incubating retinal lysates with fluorogenic substrates specific for the individual caspases. Formation of acellular capillaries was determined using the trypsin digest method. Results: Minocycline prevented hyperglycemia–induced activation of caspase–1 and subsequent interleukin–1ß production, as well as the activation of caspase–2, 6, and 8 in retinas of diabetic mice at 2 months of diabetes. Minocycline also significantly inhibited diabetes–induced formation of acellular capillaries in the retina of diabetic mice at 6 months duration. Conclusions: The results indicate that minocycline is a potent caspases inhibitor for hyperglycemia–induced caspase activation in retinal cells in vivo. Therefore, minocycline might represent a potential new drug for investigating the role of caspases and inflammation in the pathogenesis of diabetic retinopathy and might also represent a possible new drug to prevent the development of this disease.
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