Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

Ravera, Silvia; Caicci, Federico; Degan, Paolo; Maggi, Davide; Manni, Lucia; Puddu, Alessandra; Nicolò, Massimo; Traverso, Carlo Enrico; Panfoli, Isabella

doi:10.3390/antiox9111133

Cited by 9 publications

(10 citation statements)

References 61 publications

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“…In addition, we showed that SUR1-TRPM4 and SUR1-Kir 6.2 co-localized in the primate macula that is enriched in cone photoreceptors, showing a potential direct effect of glibenclamide on photoreceptors [21]. This observation is supported by a recent study showing that glibenclamide regulates photoreceptor metabolism and inhibits the production of oxygen reactive species induced by the exposure of the photoreceptor's outer segment to light [22]. Altogether, these results indicate that sulfonylureas could exert direct neuroprotective effects on the diabetes-induced retinal neurodegeneration.…”

Section: Introductionsupporting

confidence: 78%

“…Recently, Ravera et al used in vitro experiments to show that glibenclamide could interfere with the respiratory complex of rods by targeting the mitochondrial respiratory complexes I, II, and III and inhibiting the oxidative metabolism and oxidative stress. They also showed a synergistic effect of glibenclamide with metformin on reducing the production of oxygen reactive species [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

et al. 2021

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Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

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Section: Introductionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

et al. 2021

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“…In the retina, TUDCA has been shown to act on multiple cell types, through anti-apoptotic, anti-inflammatory, and antioxidant mechanisms [ 26 ]. For example, TUDCA has been reported to increase phagocytosis [ 49 ] and reduce oxidative stress in rod outer segments [ 50 ]. The rod outer segments are the sites of reactive oxygen species production and accumulation, which have been implicated as one of the pathogenic mechanisms in DR [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes

Aung

Prunty

et al. 2021

Pharmaceutics

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Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). Methods: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8–10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. Results: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. Conclusions: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy.

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“…Purified bovine POS were prepared as previously described [23]. ARPE-19 cells, previously treated with miRNA mimic or miRNA inhibitor, were pulsed with 8 µg POS in CTR or HG medium; two batches of control cells (CTR and HG) were incubated in DMEM w/o POS.…”

Section: Phagocytosis Assaysmentioning

confidence: 99%

High Glucose Impairs Expression and Activation of MerTK in ARPE-19 Cells

Puddu

Ravera

Panfoli

et al. 2022

IJMS

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MerTK (Mer Tyrosine Kinase) is a cell surface receptor that regulates phagocytosis of photoreceptor outer segments (POS) in retinal pigment epithelial (RPE) cells. POS phagocytosis is impaired in several pathologies, including diabetes. In this study, we investigate whether hyperglycemic conditions may affect MerTK expression and activation in ARPE-19 cells, a retinal pigment epithelial cellular model. ARPE-19 cells were cultured in standard (CTR) or high-glucose (HG) medium for 24 h. Then, we analyzed: mRNA levels and protein expression of MerTK and ADAM9, a protease that cleaves the extracellular region of MerTK; the amount of cleaved Mer (sMer); and the ability of GAS6, a MerTK ligand, to induce MerTK phosphorylation. Since HG reduces miR-126 levels, and ADAM9 is a target of miR-126, ARPE-19 cells were transfected with miR-126 inhibitor or mimic; then, we evaluated ADAM9 expression, sMer, and POS phagocytosis. We found that HG reduced expression and activation of MerTK. Contextually, HG increased expression of ADAM9 and the amount of sMer. Overexpression of miR-126 reduced levels of sMer and improved phagocytosis in ARPE-19 cells cultured with HG. In this study, we demonstrate that HG compromises MerTK expression and activation in ARPE-19 cells. Our results suggest that HG up-regulates ADAM9 expression, leading to increased shedding of MerTK. The consequent rise in sMer coupled to reduced expression of MerTK impairs binding and internalization of POS in ARPE-19 cells.

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Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

Cited by 9 publications

References 61 publications

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes

High Glucose Impairs Expression and Activation of MerTK in ARPE-19 Cells

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