Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy.
OBJECTIVE
Hyperglycaemia-induced mitochondrial overproduction of reactive oxygen species (ROS) is central to the pathogenesis of endothelial damage in diabetes. R-(+)-alpha-lipoic acid has advantages over classic antioxidants, as it distributes to the mitochondria, is regenerated by glycolytic flux, and has a low redox potential.


METHODS
To assess the effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy, three groups of male Wistar rats were studied: non-diabetic controls, untreated diabetic controls, and diabetic rats treated with 60 mg/kg bodyweight R-(+)-alpha-lipoic acid i.p. for 30 weeks. Quantitative retinal morphometry included acellular occluded capillaries and pericyte numbers. The effects of R-(+)-alpha-lipoic acid on parameters of oxidative and nitrative stress, AGE and its receptor and nuclear factor kappa B (NFkappaB) were assessed by immunoblotting, and NFkappaB activation by electrophoretic mobility shift assay. Angiopoietin-2 and vascular endothelial growth factors were also determined by immunoblotting.


RESULTS
After 30 weeks of diabetes, the number of acellular capillaries was significantly elevated in diabetic rats (57.1+/-10.6 acellular capillary segments [ac]/mm(2) of retinal area) compared with non-diabetic (19.8+/-5.1 ac/mm(2); p<0.001). Treatment with 60 mg/kg R-(+)-alpha-lipoic acid reduced the numbers by 88% (p<0.001 vs diabetic). Pericyte loss was also significantly inhibited in diabetic rats treated with R-(+)-alpha-lipoic acid (non-diabetic: 1,940+/-137 pericytes/mm(2)capillary area; untreated diabetic: 1,294+/-94 pericytes/mm(2)capillary area vs treated diabetic: 1,656+/-134 pericytes/mm(2); p<0.01). R-(+)-alpha-lipoic acid treatment reduced oxidative stress, normalised NFkappaB activation and angiopoietin-2 expression, and reduced vascular endothelial growth factor in the diabetic retina by 43% (p<0.0001).


CONCLUSIONS
R-(+)-alpha-lipoic acid prevents microvascular damage through normalised pathways downstream of mitochondrial overproduction of ROS, and preserves pericyte coverage of retinal capillaries, which may provide additional endothelial protection.
Lin
J
J
5th Medical Clinic, University-Clinic Mannheim, Medical Faculty of the University of Heidelberg, Heidelberg, Germany.
Bierhaus
A
A
Bugert
P
P
Dietrich
N
N
Feng
Y
Y
Vom Hagen
F
F
Nawroth
P
P
Brownlee
M
M
Hammes
H-P
HP
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008063:Thioctic Acid / Q000494:pharmacology*
D016328:NF-kappa B; D008063:Thioctic Acid