Effect of R-(+)-α-lipoic acid on experimental diabetic retinopathy

J. Lin, A. Bierhaus, P. Bugert, N. Dietrich, Y. Feng, F. Vom Hagen, P. Nawroth, M. Brownlee, H. P. Hammes

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1089-1096
Number of pages8
JournalDiabetologia
Volume49
Issue number5
DOIs
Publication statusPublished - May 1 2006

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Keywords

  • Endothelium
  • Microvascular disease
  • Oxidative stress
  • Rat retinopathy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Lin, J., Bierhaus, A., Bugert, P., Dietrich, N., Feng, Y., Vom Hagen, F., ... Hammes, H. P. (2006). Effect of R-(+)-α-lipoic acid on experimental diabetic retinopathy. Diabetologia, 49(5), 1089-1096. https://doi.org/10.1007/s00125-006-0174-y