Increased Retinal Lipid Peroxidation in Early Diabetes is not Associated with Ascorbate Depletion or Changes in Ascorbate Redox State

Fathallah, Lamia; Obrosova, Irina G.

doi:10.1006/exer.2001.0994

Cited by 12 publications

(7 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas one group reported a reduction in GSH and increase in GSSG levels as early as one-two months after induction of diabetes [47], we [257,73] and others [258] failed to demonstrate any changes in the afore mentioned parameters in rats with diabetes of similar duration. The latter is consistent with the lack of AA depletion and unchanged dehydroAA/AA ratio in the retina of rats with short-term STZ-diabetes [259]. Several groups [254,260] including ours [257,73], demonstrated downregulation of retinal SOD in STZ-diabetic rats.…”

Section: Diabetic Retinopathysupporting

confidence: 74%

Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy

Obrosova

Julius²

2005

CVP

View full text Add to dashboard Cite

Chronic complications of diabetes mellitus e.a. diabetic nephropathy, neuropathy and retinopathy develop in at least 30-50% of patients with both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes, and are the major cause of increased morbidity and mortality. The ultimate consequences of diabetes complications include renal failure, foot ulceration and amputation, and blindness. The magnitude of the problem and its economic impact make extremely important to understand the natural history of chronic diabetes complications and to identify more successful preventive and therapeutic options. The pathogenesis of diabetes complications involves multiple mechanisms. The importance of vascular component is well recognized in diabetic retinopathy, which is primarily a vascular disease, as well as diabetic nephropathy developing as a result of complex interplay between hemodynamic and metabolic factors. The importance of vascular versus non-vascular mechanisms in the pathogenesis of diabetic neuropathy remains a subject of debate. Studies in animal and cell culture models revealed that such mechanisms as increased aldose reductase activity, non-enzymatic glycation/glycoxidation, activation of protein kinase C, impaired growth factor support, enhanced oxidative/nitrosative stress, and its downstream effectors such as mitogen-activated protein kinase activation, inflammatory response, endothelin-1 overexpression and impaired Ca(++) signaling, play an important role in all three tissue-targets for diabetes complications i.e. kidney, retina and peripheral nerve. Evidence for important role of the downstream effector of free radical and oxidant-induced DNA injury, poly(ADP-ribose) polymerase activation, is emerging. This review describes recent studies addressing the role for poly(ADP-ribose) polymerase activation in diabetic nephropathy, neuropathy and retinopathy.

show abstract

Section: Diabetic Retinopathysupporting

confidence: 74%

Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy

Obrosova

Julius²

2005

CVP

View full text Add to dashboard Cite

show abstract

“…8,32,[37][38][39] One of the major sources of increased ROS in the diabetic retina is nitric oxide synthase (NOS). The significance of nitric oxide contribution to neuronal and vascular injury is indicated by the actions of NOS inhibitors in blocking neural damage in the ischemic-stroke model 40 and the NMDA neurotoxicity model, 28 and in preventing BRB breakdown in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes

El-Remessy

Al‐Shabrawey

Khalifa

et al. 2006

The American Journal of Pathology

233

168

View full text Add to dashboard Cite

Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies have been associated with oxidative stress and proinflammatory cytokines, which may operate by activating their downstream target p38 MAP kinase. In the present study, the protective effects of a nonpsychotropic cannabinoid, cannabidiol (CBD), were examined in streptozotocin-induced diabetic rats after 1, 2, or 4 weeks. Retinal cell death was determined by terminal dUTP nick-end labeling assay; BRB function by quantifying extravasation of bovine serum albumin-fluorescein; and oxidative stress by assays for lipid peroxidation, dichlorofluorescein fluorescence, and tyrosine nitration. Experimental diabetes induced significant increases in oxidative stress, retinal neuronal cell death, and vascular permeability. These effects were associated with increased levels of tumor necrosis factor-␣, vascular endothelial growth factor, and intercellular adhesion molecule-1 and activation of p38 MAP kinase, as assessed by enzyme-linked immunosorbent assay, immunohistochemistry, and/or Western blot. CBD treatment significantly reduced oxidative stress; decreased the levels of tumor necrosis factor-␣, vascular endothelial growth factor, and intercellular adhesion molecule-1; and prevented retinal cell death and vascular hyperpermeability in the diabetic retina. Consistent with these effects, CBD treatment also significantly inhibited p38 MAP kinase in the diabetic retina. These results demonstrate that CBD treatment reduces neurotoxicity, inflammation, and BRB breakdown in diabetic animals through activities that may involve inhibition of p38 MAP kinase.

show abstract

“…55 Our data showing a significant increase of lipid peroxidation in diabetic retinas are in agreement with several reports correlating formation of lipid peroxides with oxidative stress in early experimental diabetes. 12,13 The mechanism by which ROS increase VEGF gene expression has been suggested to involve an increase in VEGF mRNA stability. 54 It has also been demonstrated that ROS activate intracellular signaling events leading to the stabilization of HIF-1␣ 55 and the subsequent VEGF mRNA expression during hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] Increased formation of ROS and lipid peroxides occurs early in diabetic retinopathy. 12,13 Analyses done with endothelial cells in vitro have shown that high glucose increases the expression of eNOS.…”

mentioning

confidence: 99%

Experimental Diabetes Causes Breakdown of the Blood-Retina Barrier by a Mechanism Involving Tyrosine Nitration and Increases in Expression of Vascular Endothelial Growth Factor and Urokinase Plasminogen Activator Receptor

El-Remessy

Behzadian

Abou-Mohamed

et al. 2003

The American Journal of Pathology

186

174

View full text Add to dashboard Cite

The purpose of these experiments was to determine the specific role of reactive oxygen species (ROS) in the blood-retinal barrier (BRB) breakdown that characterizes the early stages of vascular dysfunction in diabetes. Based on our data showing that high glucose increases nitric oxide, superoxide, and nitrotyrosine formation in retinal endothelial cells, we hypothesized that excess formation of ROS causes BRB breakdown in diabetes. Because ROS are known to induce increases in expression of the well-known endothelial mitogen and permeability factor vascular endothelial growth factor (VEGF) we also examined their influence on the expression of VEGF and its downstream target urokinase plasminogen activator receptor (uPAR). After 2 weeks of streptozotocin-induced diabetes, analysis of albumin leakage confirmed a prominent breakdown of the BRB. This permeability defect was correlated with significant increases in the formation of nitric oxide, lipid peroxides, and the peroxynitrite biomarker nitrotyrosine as well as with increases in the expression of VEGF and uPAR. Treatment with a nitric oxide synthase inhibitor (N--nitro-L-arginine methyl ester, 50 mg/kg/day) or peroxynitrite scavenger (uric acid, 160 mg/kg/day) blocked the breakdown in the BRB and prevented the increases in formation of lipid peroxides and tyrosine nitration as well as the increases in expression of VEGF and uPAR. Taken together, these data indicate that early diabetes causes breakdown of the BRB by a mechanism involving the action of reactive nitrogen species in promoting expression of VEGF and uPAR.

show abstract

Increased Retinal Lipid Peroxidation in Early Diabetes is not Associated with Ascorbate Depletion or Changes in Ascorbate Redox State

Cited by 12 publications

References 40 publications

Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy

Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy

Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes

Experimental Diabetes Causes Breakdown of the Blood-Retina Barrier by a Mechanism Involving Tyrosine Nitration and Increases in Expression of Vascular Endothelial Growth Factor and Urokinase Plasminogen Activator Receptor

Contact Info

Product

Resources

About