Theophylline Inhibits Capillary Degeneration in Early Diabetic Retinopathy.

Purpose: Recent evidence suggests that simultaneous inhibition of multiple diabetes-induced molecular abnormalities is a valuable approach toward inhibiting the development of early stages of diabetic retinopathy (DR). The methylxanthine, theophylline acts by multiple mechanisms in different diseases, and we investigated its effect on the development of lesions of early DR. Methods: Wild-type C57Bl/6J male mice were made diabetic with streptozotocin at two to three months of age, and some were given theophylline or structurally related analogs for one to two months to assess effects on visual function and biochemical and physiological abnormalities in the retina, or for eight months to assess retinal vascular histopathology. Effects of theophylline on leukocytes were examined ex vivo, because leukocytes contribute to the retinal vascular pathology of diabetes. Results: Retinal superoxide generation, expression of inflammatory proteins, leukocyte-mediated cytotoxicity against retinal endothelial cells, and degeneration of retinal capillaries were significantly increased in retinas of control diabetic mice, and theophylline inhibited each of these abnormalities. Of recognized actions of theophylline (adenosine receptor antagonist, antioxidant and anti-inflammatory agent, inducer of histone deacetylase activity, inhibitor of phosphodiesterases), the inhibition of phosphodiesterases, oxidative stress and inflammation seem most likely to account for the beneficial effects of the drug in DR. In contrast to the beneficial effect of theophylline on capillary degeneration, it did not inhibit the diabetes-induced dysfunction of the neural retina. Conclusions: Theophylline significantly inhibited the degeneration of retinal capillaries in early DR and can help investigate mechanistic differences in the pathogenesis of retinal capillary degeneration and neural dysfunction in diabetes.