The AGE Inhibitor Pyridoxamine Inhibits Development of Retinopathy in Experimental Diabetes

The AGE Inhibitor Pyridoxamine Inhibits Development of Retinopathy in Experimental Diabetes Alan Stitt 1 , Thomas A. Gardiner 1 , Nathan L. Anderson 2 , Paul Canning 1 , Norma Frizzell 1 , Noel Duffy 1 , Cliona Boyle 1 , Andrzej S. Januszewski 2 , Mark Chachich 2 , John W. Baynes 2 and Suzanne R. Thorpe 2 1 Department of Ophthalmology, Institute of Clinical Science, The Royal Victoria Hospital, Queen’s University of Belfast, Belfast, Northern Ireland 2 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina Abstract We examined the ability of pyridoxamine (PM), an inhibitor of formation of advanced glycation end products (AGEs) and lipoxidation end products (ALEs), to protect against diabetes-induced retinal vascular lesions. The effects of PM were compared with the antioxidants vitamin E (VE) and R-α-lipoic acid (LA) in streptozotocin-induced diabetic rats. Animals were given either PM (1 g/l drinking water), VE (2,000 IU/kg diet), or LA (0.05%/kg diet). After 29 weeks of diabetes, retinas were examined for pathogenic changes, alterations in extracellular matrix (ECM) gene expression, and accumulation of the immunoreactive AGE/ALE N ε -(carboxymethyl)lysine (CML). Acellular capillaries were increased more than threefold, accompanied by significant upregulation of laminin immunoreactivity in the retinal microvasculature. Diabetes also increased mRNA expression for fibronectin (2-fold), collagen IV (1.6-fold), and laminin β chain (2.6-fold) in untreated diabetic rats compared with nondiabetic rats. PM treatment protected against capillary drop-out and limited laminin protein upregulation and ECM mRNA expression and the increase in CML in the retinal vasculature. VE and LA failed to protect against retinal capillary closure and had inconsistent effects on diabetes-related upregulation of ECM mRNAs. These results indicate that the AGE/ALE inhibitor PM protected against a range of pathological changes in the diabetic retina and may be useful for treating diabetic retinopathy. Footnotes Address correspondence and reprint requests to Professor Alan Stitt, Department of Ophthalmology, Institute of Clinical Science, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland. E-mail: a.stitt{at}qub.ac.uk . Received for publication 18 February 2002 and accepted in revised form 3 June 2002. A.S. has received stock options and consulting fees from BioStratum as a member of their Scientific Advisory Board, as well as research s