TY - JOUR
T1 - Effect of R-(+)-α-lipoic acid on experimental diabetic retinopathy
AU - Lin, J.
AU - Bierhaus, A.
AU - Bugert, P.
AU - Dietrich, N.
AU - Feng, Y.
AU - Vom Hagen, F.
AU - Nawroth, P.
AU - Brownlee, M.
AU - Hammes, H. P.
N1 - Funding Information:
Acknowledgements The study was supported by the Deutsche Forschungsgemeinschaft (Ha 1755/7-2 to H.-P. Hammes, Y. Feng and N. Dietrich; Na 138/5-3; SFB 405 to P. P. Nawroth.), the Deutsche Diabetes-Gesellschaft (to H.-P. Hammes, J. Lin and A. Bierhaus), the European Foundation for the Study of Diabetes (to F. v. Hagen, H.-P. Hammes and A. Bierhaus) and Viatris Pharma (Frankfurt/Main, Germany) (to H.-P. Hammes).
PY - 2006/5
Y1 - 2006/5
N2 - Aims/hypothesis: Hyperglycaemia-induced mitochondrial overproduction of reactive oxygen species (ROS) is central to the pathogenesis of endothelial damage in diabetes. R-(+)-α-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-(+)-α-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-(+)-α-lipoic acid i.p. for 30 weeks. Quantitative retinal morphometry included acellular occluded capillaries and pericyte numbers. The effects of R-(+)-α-lipoic acid on parameters of oxidative and nitrative stress, AGE and its receptor and nuclear factor kappa B (NFκB) were assessed by immunoblotting, and NFκB 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]/mm2 of retinal area) compared with non-diabetic (19.8±5.1 ac/mm2; p<0.001). Treatment with 60 mg/kg R-(+)-α-lipoic acid reduced the numbers by 88% (p<0.001 vs diabetic). Pericyte loss was also significantly inhibited in diabetic rats treated with R-(+)-α-lipoic acid (non-diabetic: 1,940±137 pericytes/mm2capillary area; untreated diabetic: 1,294±94 pericytes/mm2capillary area vs treated diabetic: 1,656±134 pericytes/mm2; p<0.01). R-(+)-α-lipoic acid treatment reduced oxidative stress, normalised NFκB activation and angiopoietin-2 expression, and reduced vascular endothelial growth factor in the diabetic retina by 43% (p<0.0001). Conclusions/ interpretation: R-(+)-α-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.
AB - Aims/hypothesis: Hyperglycaemia-induced mitochondrial overproduction of reactive oxygen species (ROS) is central to the pathogenesis of endothelial damage in diabetes. R-(+)-α-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-(+)-α-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-(+)-α-lipoic acid i.p. for 30 weeks. Quantitative retinal morphometry included acellular occluded capillaries and pericyte numbers. The effects of R-(+)-α-lipoic acid on parameters of oxidative and nitrative stress, AGE and its receptor and nuclear factor kappa B (NFκB) were assessed by immunoblotting, and NFκB 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]/mm2 of retinal area) compared with non-diabetic (19.8±5.1 ac/mm2; p<0.001). Treatment with 60 mg/kg R-(+)-α-lipoic acid reduced the numbers by 88% (p<0.001 vs diabetic). Pericyte loss was also significantly inhibited in diabetic rats treated with R-(+)-α-lipoic acid (non-diabetic: 1,940±137 pericytes/mm2capillary area; untreated diabetic: 1,294±94 pericytes/mm2capillary area vs treated diabetic: 1,656±134 pericytes/mm2; p<0.01). R-(+)-α-lipoic acid treatment reduced oxidative stress, normalised NFκB activation and angiopoietin-2 expression, and reduced vascular endothelial growth factor in the diabetic retina by 43% (p<0.0001). Conclusions/ interpretation: R-(+)-α-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.
KW - Endothelium
KW - Microvascular disease
KW - Oxidative stress
KW - Rat retinopathy
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U2 - 10.1007/s00125-006-0174-y
DO - 10.1007/s00125-006-0174-y
M3 - Article
C2 - 16520919
AN - SCOPUS:33646413409
SN - 0012-186X
VL - 49
SP - 1089
EP - 1096
JO - Diabetologia
JF - Diabetologia
IS - 5
ER -
