Diabetic retinopathy remains the fifth leading cause of preventable blindness worldwide and an increasing problem for veterans. Interventions to prevent progression of diabetic retinopathy are limited to improved glycemic control (a challenging goal for all diabetic patients) and to laser photocoagulation (available only for advanced stages of retinopathy). We and others have reported that adrenergic signaling is lost in the diabetic retina, suggesting that development of novel agents to restore autonomic homeostasis is necessary. Unfortunately, currently available adrenergic agents are associated with adverse systemic or non-specific effects. These problems inspired our group to synthesize compound 49b, a novel and selective -adrenergic receptor agonist, as a potential paradigm shift in the prevention of diabetic retinopathy. Our preliminary data suggest that compound 49b prevents the formation of degenerate capillaries, which involves degenerate capillary formation, which are the hallmark pathology noted in the diabetic retinal vasculature. In addition to preventing degenerate capillaries in vivo, compound 49b prevents the cleavage of caspase 3, a well- established marker of apoptosis, in retinal endothelial cells (REC) in vitro, suggesting that Compound 49b can decrease apoptosis. In the oxygen-induced model of retinopathy, others have associated increased levels of insulin-like growth factor binding protein-3 (IGFBP-3) with protection from REC apoptosis. Furthermore, using the streptozotocin-induced diabetic rat model, we observed that chronic insulin deficiency reduced IGFBP-3 protein levels in whole retinal lysates, but topical application of compound 49b to the eye restored retinal IGFBP-3 to its control level in these insulin- deficient rats. Thu, we hypothesize that compound 49b prevents the critical vascular damage underlying diabetic retinopathy in part by restoring IGFBP-3 levels in retinal endothelial cells. This project focuses on a deeper understanding of the mechanisms underlying this protective action in a type II rat model, which will expedite movement of this novel drug into human clinical trials.
Veterans have increased levels of type II diabetes over the general population. This study will dissect the cellular mechanisms of the protective role of ?-adrenergic receptor agonists on IGFBP3 levels and retinal endothelial cell apoptosis in a type II diabetic rat model, providing data to move toward human clinical trials. !
|He, Hui; Williams-Guy, Kimberly; Pagadala, Jayaprakash et al. (2014) A sensitive and fast LC-MS/MS method for determination of ?-receptor agonist JP-49b: application to a pharmacokinetic study in rats. J Chromatogr B Analyt Technol Biomed Life Sci 953-954:86-91|