In This Issue of Diabetes

Edited by Helaine E. Resnick, PhD, MPH

Drug Repurposing: Potential Utility of Paroxetine in Diabetes Complications

Data presented in this issue of Diabetes (p. 953) raise the potential of repurposing paroxetine for future exploratory clinical trials in patients with diabetes vascular complications. Work by Gerö et al. examines phenotypic screening as a means to identify existing compounds that may impact key mechanisms involved in promoting diabetes complications. Reactive oxygen species (ROS) formation is thought to be involved in the pathogenesis of diabetic endothelial dysfunction, which in turn suggests ROS involvement in both large- and small-vessel complications. Gerö et al. conducted the first systematic survey to identify drugs and drug-like molecules with the ability to protect endothelial cells from hyperglycemic mitochondrial ROS overproduction. After phenotypic screening in endothelial cells exposed to elevated extracellular glucose, fewer than 20 compounds from a focused library of more than 6,000 compounds met criteria for significant inhibition of ROS production without adverse effects on cell viability. Some of these were glucocorticoids and nonsteroidal anti-inflammatory compounds. The investigators chose to focus on characterizing paroxetine, a commonly used antidepressant agent. Importantly, the wide clinical use and acceptance of paroxetine suggests that, if effective in reducing ROS, this compound might be efficiently repurposed for experimental therapy of diabetes complications. In a series of in vitro experiments, paroxetine reduced hyperglycemia-induced mitochondrial ROS formation and mitochondrial protein oxidation, as well as mitochondrial and nuclear DNA damage. Notably, paroxetine did not interfere with mitochondrial electron transport or cellular bioenergetics. Decomposition studies demonstrated that the primary site of paroxetine’s antioxidant effect resides within its sesamol moiety. In a further series of experiments, aortic rings isolated from streptozotocin-injected diabetic rats showed endothelial dysfunction, as evidenced by an impaired relaxation …

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This Article

  1. doi: 10.2337/db13-ti03 Diabetes vol. 62 no. 3 667-668
  1. Free via Open Access: OA