The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes.
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-alpha-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( epsilon )-(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 beta 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.
Stitt
Alan
A
Department of Ophthalmology, Institute of Clinical Science, The Royal Victoria Hospital, Queen's University of Belfast, Belfast, Northern Ireland. a.stitt@qub.ac.uk
Gardiner
Thomas A
TA
Alderson
Nathan L
NL
Canning
Paul
P
Frizzell
Norma
N
Duffy
Noel
N
Boyle
Cliona
C
Januszewski
Andrzej S
AS
Chachich
Mark
M
Baynes
John W
JW
Thorpe
Suzanne R
SR
Anderson
Nathan L
NL
D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000473:pathology / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007797:Laminin / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D011733:Pyridoxamine / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology
D017127:Glycation End Products, Advanced; D007797:Laminin; D012333:RNA, Messenger; D011733:Pyridoxamine; C048496:N(6)-carboxymethyllysine; D008239:Lysine