title: Ascorbic acid repletion: A possible therapy for diabetic macular edema?
abstract: Macular edema poses a significant risk for visual loss in persons with diabetic retinopathy. It occurs when plasma constituents and fluid leak out of damaged retinal microvasculature in the area of the macula, causing loss of central vision. Apoptotic loss of pericytes surrounding capillaries is perhaps the earliest feature of diabetic vascular damage in the macula, which is also associated with dysfunction of the endothelium and loss of the otherwise very tight endothelial permeability barrier. Increased oxidative stress is a key feature of damage to both cell types, mediated by excess superoxide from glucose-induced increases in mitochondrial metabolism, as well as by activation of the receptor for advanced glycation end products (RAGE). The latter in turn activates multiple pathways, some of which lead to increased oxidative stress, such as those involving NF-ĸB, NADPH oxidase, and endothelial nitric oxide synthase. Such cellular oxidative stress is associated with low cellular and plasma ascorbic acid levels in many subjects with diabetes in poor glycemic control. Whether repletion of low ascorbate in retinal endothelium and pericytes might help to prevent diabetic macular edema is unknown. However, cell culture studies show that the vitamin prevents high-glucose and RAGE-induced apoptosis in both cell types, that it preserves nitric oxide generated by endothelial cells, and that it tightens the leaky endothelial permeability barrier. Although these findings need to be confirmed in pre-clinical animal studies, it is worth considering clinical trials to determine whether adequate ascorbate repletion is possible and whether it might help to delay or even reverse early diabetic macular edema.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6303, United States. Electronic address: james.may@vanderbilt.edu.
authors.forename: James M
authors.initials: JM
authors.lastname: May
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000627:therapeutic use*; D003930:Diabetic Retinopathy / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008269:Macular Edema / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D012160:Retina / Q000187:drug effects / Q000473:pathology; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; D001205:Ascorbic Acid
keywords: Ascorbate; Diabetes; Endothelial cells; Macular edema; Pericytes