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

Lin, Jing; Bierhaus, Angelika; Bugert, Petra; Dietrich, Nadine; Feng, Yuxi; Hagen, Franziska vom; Nawroth, Peter P.; Brownlee, Michael; Hammes, Hans‐Peter

doi:10.1007/s00125-006-0174-y

Cited by 88 publications

(75 citation statements)

References 42 publications

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“…This hypothesis is consistent with a previous finding that the return to good glycaemic control in rats after 6 months of very poor control was ineffective in decreasing 3-NY levels or other markers of oxidative stress in the retina of these diabetic animals [12]. Moreover, the effect of ALA in our study supports the finding of Lin et al, showing protective effects of ALA in experimental diabetic retinopathy through the inhibition of oxidative and nitrosative stress [36]. The 1 week duration of the 'memory' of high glucose stress is too long to be explained by simple signalling mechanisms or the half-lives of messenger RNA or protein.…”

Section: Discussionsupporting

confidence: 94%

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

et al. 2007

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Aims/hypothesis A long-term 'memory' of hyperglycaemic stress, even when glycaemia is normalised, has been previously reported in endothelial cells. In this report we sought to duplicate and extend this finding. Materials and methods HUVECs and ARPE-19 retinal cells were incubated in 5 or in 30 mmol/l glucose for 3 weeks or subjected to 1 week of normal glucose after being exposed for 2 weeks to continuous high glucose. HUVECs were also treated in this last condition with several antioxidants. Similarly, four groups of rats were studied for 3 weeks: (1) normal rats; (2) diabetic rats not treated with insulin; (3) diabetic rats treated with insulin during the last week; and (4) diabetic rats treated with insulin plus α-lipoic acid in the last week. Results In human endothelial cells and ARPE-19 retinal cells in culture, as well as in the retina of diabetic rats, levels of the following markers of high glucose stress remained induced for 1 week after levels of glucose had normalised: protein kinase C-β, NAD(P)H oxidase subunit p47phox, BCL-2-associated X protein, 3-nitrotyrosine, fibronectin, poly(ADPribose) Blockade of reactive species using different approaches, i.e. the mitochondrial antioxidant α-lipoic acid, overexpression of uncoupling protein 2, oxypurinol, apocynin and the poly(ADP-ribose) polymerase inhibitor PJ34, interrupted the induction both of high glucose stress markers and of the fluorescent reactive oxygen species (ROS) probe CM-H 2 DCFDA in human endothelial cells. Similar results were obtained in the retina of diabetic rats with α-lipoic acid added to the last week of normalised glucose. Conclusions/interpretation These results provide proofof-principle of a ROS-mediated cellular persistence of vascular stress after glucose normalisation.

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Section: Discussionsupporting

confidence: 94%

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

et al. 2007

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“…Our observation that hyperglycaemia-induced upregulation of Ang-2 is reduced by erythropoietin treatment, together with the notion that pericytes are preserved in erythropoietin-treated diabetic rats, is consistent with recent data. Hyperglycaemia increases methylglyoxal formation and ANG-2 production [14,39]. A link between elevated methylglyoxal and ANG-2 levels is suggested by the findings of Yao et al that hyperglycaemia-induced formation of methylglyoxal modifies the transcriptional co-repressor (mSin3A), resulting in increased recruitment of O-linked N-acetylglucosamine transferase to an mSin3A-transcription factor specificity protein 3 (Sp3) complex and the subsequent increased modification of Sp3 by O-linked N-acetylglucosamine [14].…”

Section: Discussionmentioning

confidence: 99%

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

et al. 2010

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Aims/hypothesis Diabetic retinopathy is the result of increased oxidative and nitrosative stress induced by chronic hyperglycaemia, and affects the vasculature and the neuroglia. Erythropoietin is a neuroprotective and an endothelial survival factor. We assessed the effect of suberythropoietic epoetin delta doses on variables of oxidative stress in target tissues of diabetic complications and on pericyte loss in the diabetic retina. Methods We administered epoetin delta to streptozotocininduced diabetic Wistar rats at doses of 384 IU/kg body weight once weekly or 128 IU/kg body weight three times a week. The treatment lasted for 3 months. Oxidative stress and formation of AGEs were assessed by immunoblotting, expression of Ang-2 (also known as Angpt2) by RT-PCR, activation of protein kinase B (AKT) and heat shock protein (HSP)-27 levels by immunofluorescence, and incipient retinal vascular changes by quantitative morphometry of retinal digest preparations. Results Diabetes increased variables of oxidative stress and nitrosative stress (N ε -carboxymethyl-lysine, nitrotyrosine and methylglyoxal-type AGEs) in retina, kidney and heart of diabetic rats. Epoetin delta reduced oxidative and nitrosative stress in all tissues, and AGEs in the retina. It also reduced increased retinal Ang-2 expression and pericyte loss, and ameliorated p-AKT and HSP-27 levels. Conclusions/interpretation Epoetin delta has antioxidative properties in organs affected by diabetes and may prevent incipient microvascular damage in the diabetic retina.

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“…An important example is the oxidative inactivation of prostacyclin synthase, a critical anti-atherosclerosis endothelial enzyme [10]. For this reason, we combined the antioxidant α-lipoic acid with benfotiamine [4]. In this pilot study we report that treatment with oral benfotiamine plus α-lipoic acid normalises several complications-causing pathways in patients with type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…It does so by activating the enzyme transketolase. α-Lipoic acid, a potent antioxidant, has also been reported to reduce diabetic microvascular and macrovascular complications in animal models [4,5]. To determine whether benfotiamine in combination with α-lipoic acid would normalise markers of reactive oxygen species-induced pathways of complications in humans, we performed a pilot study in participants with type 1 diabetes using one daily dose of benfotiamine in combination with α-lipoic acid.…”

Section: Introductionmentioning

confidence: 99%

Oral benfotiamine plus α-lipoic acid normalises complication-causing pathways in type 1 diabetes

Edelstein

Brownlee

2008

Diabetologia

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Aims/hypothesis We determined whether fixed doses of benfotiamine in combination with slow-release α-lipoic acid normalise markers of reactive oxygen species-induced pathways of complications in humans. Methods Male participants with and without type 1 diabetes were studied in the General Clinical Research Centre of the Albert Einstein College of Medicine. Glycaemic status was assessed by measuring baseline values of three different indicators of hyperglycaemia. Intracellular AGE formation, hexosamine pathway activity and prostacyclin synthase activity were measured initially, and after 2 and 4 weeks of treatment. Results In the nine participants with type 1 diabetes, treatment had no effect on any of the three indicators used to assess hyperglycaemia. However, treatment with benfotiamine plus α-lipoic acid completely normalised increased AGE formation, reduced increased monocyte hexosaminemodified proteins by 40% and normalised the 70% decrease in prostacyclin synthase activity from 1,709±586 pg/ml 6-keto-prostaglandin F 1α to 4,696±533 pg/ml. Conclusions/interpretation These results show that the previously demonstrated beneficial effects of these agents on complication-causing pathways in rodent models of diabetic complications also occur in humans with type 1 diabetes.Trial registration: NCT00703989

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

Cited by 88 publications

References 42 publications

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

Oral benfotiamine plus α-lipoic acid normalises complication-causing pathways in type 1 diabetes

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