Diabetic Retinopathy - Treatment

Alpha Lipoic Acid - updated: 15 March 2008

Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats

Diabetes. 2004 Dec;53(12):3233-8

Kowluru RA, Odenbach S.

Oxidative stress is increased in the retina in diabetes, and it is considered to play an important role in the development of retinopathy. alpha-Lipoic acid, a thiol antioxidant, has been shown to have beneficial effects on polyneuropathy and on the parameters of oxidative stress in various tissues, including nerve, kidney, and retina. The purpose of this study was to examine the effect of alpha-lipoic acid on retinal capillary cell apoptosis and the development of pathology in diabetes. Retina was used from streptozotocin-induced diabetic rats receiving diets supplemented with or without alpha-lipoic acid (400 mg/kg) for 11 months of diabetes. Capillary cell apoptosis (by terminal transferase-mediated dUTP nick-end labeling) and formation of acellular capillaries were investigated in the trypsin-digested retinal microvessels. The effect of alpha-lipoic acid administration on retinal 8-hydroxy-2'deoxyguanosine (8-OHdG) and nitrotyrosine levels was determined by enzyme-linked immunosorbent assay. alpha-Lipoic acid administration for the entire duration of diabetes inhibited capillary cell apoptosis and the number of acellular capillaries in the retina, despite similar severity of hyperglycemia in the two diabetic groups (with and without alpha-lipoic acid). Retinal 8-OHdG and nitrotyrosine levels were increased by over twofold and 70%, respectively, in diabetes, and alpha-lipoic acid administration inhibited these increases. Our results demonstrate that the long-term administration of alpha-lipoic acid has beneficial effects on the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine in the retina. alpha-Lipoic acid supplementation represents an achievable adjunct therapy to help prevent vision loss in diabetic patients.

Publication Types:

• Animal Study

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

Diabetologia. 2006 May;49(5):1089-96. Epub 2006 Mar 7

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

AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.

Publication Types:

• Animal Study

R-(+)-alpha-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E681-9. Epub 2007 Jun 12

Artwohl M, Muth K, Kosulin K, de Martin R, Hölzenbein T, Rainer G, Freudenthaler A, Huttary N, Schmetterer L, Waldhäusl WK, Baumgartner-Parzer SM.

Lipoic acid was recently demonstrated to improve endothelial dysfunction or retinopathy not only in rats but also in diabetic patients. We tested the hypothesis that R-(+)-alpha-lipoic acid (LA) directly affects human endothelial cell (EC) function (e.g., apoptosis, proliferation, and protein expression), independent of the cells' vascular origin. Macrovascular EC (macEC), isolated from umbilical (HUVEC) and adult saphenous veins and from aortae, as well as microvascular EC (micEC) from retinae, skin, and uterus, were exposed to LA (1 mumol/l-1 mmol/l) with/without different stimuli (high glucose, TNF-alpha, VEGF, wortmannin, LY-294002). Apoptosis, proliferation, cell cycle distribution, and protein expression were determined by DNA fragmentation assays, [(3)H]thymidine incorporation, FACS, and Western blot analyses, respectively. In macro- and microvascular EC, LA (1 mmol/l) reduced (P < 0.05) basal (macEC, -36 +/- 4%; micEC, -46 +/- 6%) and stimulus-induced (TNF-alpha: macEC, -75 +/- 11%; micEC, -68 +/- 13%) apoptosis. In HUVEC, inhibition of apoptosis by LA (500 mumol/l) was paralleled by reduction of NF-kappaB. LA's antiapoptotic activity was reduced by PI 3-kinase inhibitors (wortmannin, LY-294002), being in line with LA-induced Akt phosphorylation (Ser(437), +159 +/- 43%; Thr(308), +98 +/- 25%; P < 0.01). LA (500 mumol/l) inhibited (P < 0.001) proliferation of macEC (-29 +/- 3%) and micEC (-29 +/- 3%) by arresting the cells at the G(1)/S transition due to an increased ratio of cyclin E/p27(Kip) (4.2-fold), upregulation of p21(WAF-1/Cip1) (+104 +/- 21%), and reduction of cyclin A (-32 +/- 11%), of hyperphosphorylated retinoblastoma protein (macEC: -51 +/- 7%; micEC: -50 +/- 15%), and of E2F-1 (macEC: -48 +/- 3%; micEC: -31 +/- 10%). LA's ability to inhibit apoptosis and proliferation of ECs could beneficially affect endothelial dysfunction, which precedes manifestation of late diabetic vascular complications.

Impaired apparent ion demand in experimental diabetic retinopathy: correction by lipoic Acid

Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4753-8

Berkowitz BA, Roberts R, Stemmler A, Luan H, Gradianu M.

PURPOSE: To test the hypothesis that early in the course of diabetes, apparent ion demand within the retina is impaired and may be corrected by alpha-lipoic acid (LPA), a drug that inhibits vascular histopathology. METHODS: Intraretinal manganese ion uptake and retinal thickness were measured from high-resolution manganese-enhanced MRI (MEMRI) data of control and streptozocin diabetic male Sprague-Dawley (SD) rats and of control and diabetic female Lewis rats with and without treatment with LPA. In a subgroup of male SD rats, blood-retinal barrier (BRB) integrity was also assessed with dynamic contrast-enhanced MRI. In addition, ion-coupled plasma-mass spectrometry (ICP-MS) was used to measure baseline whole manganese levels from retinas of control and diabetic rats. RESULTS: Manganese ion uptake by receptor and postreceptor retina was subnormal in each untreated diabetic groups, and these deficiencies could be corrected with LPA treatment. ICP-MS studies found no differences in baseline retinal manganese concentration between control and diabetic rats. In 3-month-old diabetic male SD rats, total and postreceptor retinal thickness increased (P < 0.05) without loss of BRB integrity. In contrast, in untreated and treated diabetic female Lewis rats, retinal thicknesses were normal. CONCLUSIONS: The present results support the hypothesis that LPA can correct the impaired apparent ion demand in experimental diabetic retinopathy.

Publication Types:

• animal Study

alpha-lipoic acid corrects late-phase supernormal retinal oxygenation response in experimental diabetic retinopathy

Invest Ophthalmol Vis Sci. 2006 Sep;47(9):4077-82

Roberts R, Luan H, Berkowitz BA.

PURPOSE: To test the hypothesis that preventative alpha-lipoic acid (LPA) treatment corrects an abnormal retinal oxygenation response in experimental diabetic retinopathy. METHODS: Retinal oxygenation (DeltaPO2) was measured by MRI before (room air [ra]) and during a 4-minute carbogen inhalation challenge in five groups: control Sprague-Dawley (SD) and Lewis (LEW) rats, 3- to 4-month diabetic SD and LEW rats, and 4-month diabetic LEW rats preventatively treated with a chow LPA admix (400 mg/kg per chow). Comparisons were made between the initial 2 minutes of oxygenation change (measured using ra and first carbogen periods [t1 - ra]) and the next 2-minute change (assessed with first and second carbogen periods [t2-t1]) for superior and inferior hemiretinal DeltaPO2. RESULTS: In control SD rats, DeltaPO2(t1-ra) > DeltaPO2(t2-t1) (P <0.05) was found panretinally. In diabetic SD rats, the superior, but not the inferior, hemiretina had subnormal DeltaPO2(t1- ra) (P < 0.05) and supernormal DeltaPO2(t2-t1) (P < 0.05). In control LEW rats, DeltaPO2(t1-ra) and DeltaPO2(t2-t1) were not significantly different (P > 0.05). Also, control and diabetic LEW rat panretinal DeltaPO2(t1-ra) were lower (P < 0.05) than in the respective SD groups. In diabetic LEW rats, a supernormal (P < 0.05) panretinal DeltaPO2(t2-t1) was found that could be corrected with preventative LPA treatment. CONCLUSIONS: These data support the hypothesis and suggest that the influence of strain differences on the interpretation of retinovascular DeltaPO2 as a surrogate of drug treatment efficacy for diabetic retinopathy may be minimized by measuring a late-phase supernormal response. The LPA data raise the possibility that oxidative stress contributes to diabetes-induced supernormal DeltaPO2.

Publication Types:

• Animal Study

Alpha-lipoic acid protects the retina against ischemia-reperfusion

Neuropharmacology. 2002 Nov;43(6):1015-25

Chidlow G, Schmidt KG, Wood JP, Melena J, Osborne NN.

The aim of this study was to examine whether the antioxidant alpha-lipoic acid protects retinal neurons from ischemia-reperfusion injury. Rats were injected intraperitoneally with either vehicle or alpha-lipoic acid (100 mg/kg) once daily for 11 days. On the third day, ischemia was delivered to the rat retina by raising the intraocular pressure above systolic blood pressure for 45 min. The electroretinogram was measured prior to ischemia and 5 days after reperfusion. Rats were killed 5 or 8 days after reperfusion and the retinas were processed for immunohistochemistry and for determination of mRNA levels by RT-PCR. Ischemia-reperfusion caused a significant reduction of the a- and b-wave amplitudes of the electroretinogram, a decrease in nitric oxide synthase and Thy-1 immunoreactivities, a decrease of retinal ganglion cell-specific mRNAs and an increase in bFGF and CNTF mRNA levels. All of these changes were clearly counteracted by alpha-lipoic acid. Moreover, in mixed rat retinal cultures, alpha-lipoic acid partially counteracted the loss of GABA-immunoreactive neurons induced by anoxia. The results of the study demonstrate that alpha-lipoic acid provides protection to the retina as a whole, and to ganglion cells in particular, from ischemia-reperfusion injuries. alpha-Lipoic acid also displayed negligible affinity for voltage-dependent sodium and calcium channels.

Publication Types:

• Animal Study

Publication Types:

• Review