Impaired Apparent Ion Demand in Experimental Diabetic Retinopathy: Correction by Lipoic Acid

Berkowitz, Bruce A.; Roberts, Robin; Stemmler, Ann J.; Luan, Hongmei; Gradianu, Marius

doi:10.1167/iovs.07-0433

Cited by 44 publications

(77 citation statements)

References 37 publications

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“…In any event, based on the literature it was unclear if retinaldehydes would have antioxidant properties in the present context of the retina and diabetes. 4,5,29,74 Our data present undisputable evidence that retinoids administered systemically lower the level of retinal oxidative stress and correct three assays of rod function (transretinal recordings, MEMRI, and ADC), an unlikely scenario if all-trans is toxic in our diabetic model. 6 These results may seem surprising given other evidence that strong light in non-diabetic models increased levels of alltrans-retinaldehyde, which presumably activated NADPH oxidase, thus killing the photoreceptor.…”

Section: Discussionmentioning

confidence: 51%

“…1,[3][4][5][6] Although the nature of the rod dysfunction is not entirely understood, it likely involves dysregulation of photoreceptor ion channels. 5,[7][8][9][10][11] For example, rod cell calcium channels, which are normally open in the dark, are paradoxically closed in dark adapted diabetic mice as measured by manganeseenhanced MRI (MEMRI), the imaging modality of choice for studying retinal L-type calcium channel regulation in vivo. 3,[12][13][14][15][16][17][18][19][20][21][22] In an initial study, diabetic mice treated with a single intraperitoneal (i.p.)…”

mentioning

confidence: 99%

“…5,11,[29][30][31] Thus, we wondered if, as previously suggested by data in ex vivo assays, [32][33][34][35] retinaldehydes might be acting as antioxidants in diabetic mouse retina. If so, this could explain the beneficial impact of systemic retinaldehydes on improving dysfunctional rods in diabetes in vivo.…”

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confidence: 99%

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Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Berkowitz

Kern

Bissig

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested.METHODS. Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cisretinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde).RESULTS. Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by~21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by~55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde.CONCLUSIONS. Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism.

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Section: Discussionmentioning

confidence: 51%

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confidence: 99%

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Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Berkowitz

Kern

Bissig

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Supporting its safety, the vector did not modify the retinal vascular bed and the ERG in non-diabetic rats. Finally, we explored the thinning of the retina which, owing to the neurodegeneration of the inner retina, occurs in diabetic humans, [42][43][44][45] and in some, [46][47][48][49] but not all, 50 diabetic rodent studies. We confirmed that retinal thinning does not occur at 6 weeks post-STZ-treatment, 47,49 and showed that the AAV2 vasoinhibin vector did not modify it.…”

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

confidence: 99%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

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“…It was reported that the levels of H 2 0 2 , which is a specific quantitative biochemical marker for oxidative stress, is increased with the functional severity of hyperglycemia in the retina of diabetic animals. However, supplement of antioxidant agents such as Aminoguanidine and alpha-lipoic acid was shown to improve retinal function in diabetic animals [42,43]. MMP-2 and -9, induced in response to hyperglycemia are associated with increased ROS (such as hydroxyl radicals and superoxide) production and decreased ROS scavengers (i.e., antioxidants) in the retina-derived endothelial cells in diabetes [26,37].…”

Section: Mmps and Oxidative Stressmentioning

confidence: 99%

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

Mohammad

Siddiquei

2012

j ocul biol dis inform

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Diabetic retinopathy represents the most common causes of vision loss in patients affected by diabetes mellitus. The cause of vision loss in diabetic retinopathy is complex and remains incompletely understood. One of the earliest changes in the development of retinopathy is the accelerated apoptosis of retinal microvascular cells and the formation of acellular capillaries by unknown mechanism. Results of a recent research suggest an important role of matrix metalloproteinases (MMPs) in the development of diabetic retinopathy. MMPs are a large family of proteinases that remodel extracellular matrix components, and under pathological condition, its induction is considered as a negative regulator of cell survival; and in diabetes, latent MMPs are activated in the retina and its capillary cells, and activation of MMP-2 and -9 induces apoptosis of retinal capillary cells. This review will focus on the MMP-2 and MMP-9 in the diabetic retina with special reference to oxidative stress, mitochondria dysfunction, inflammation and angiogenesis, as well as summarizing the current information linking these proteins to pathogenesis of diabetic retinopathy.

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Impaired Apparent Ion Demand in Experimental Diabetic Retinopathy: Correction by Lipoic Acid

Abstract: The present results support the hypothesis that LPA can correct the impaired apparent ion demand in experimental diabetic retinopathy.

Cited by 44 publications

References 37 publications

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Role of matrix metalloproteinase-2 and -9 in the development of diabetic retinopathy

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