Prevention of Retinal Vessel Changes Associated With Diabetic Retinopathy in Galactose-Fed Dogs by Aldose Reductase Inhibitors

Kador, Peter F.; Akagi, Yoshio; Takahashi, Yukio; Ikebe, H; Wyman, Milton; Kinoshita, Jin H.

doi:10.1001/archopht.1990.01070110117035

Cited by 134 publications

(56 citation statements)

References 15 publications

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“…However, the retinal microangiopathy developed by dogs fed a 30% galactose diet was just delayed or not prevented at all [118] by the AR inhibitor sorbinil. One group of researchers revealed that sorbinil was metabolized more abruptly in dogs as compared to rats, yielding unpredictably a shorter plasma half-life [119]. Results of the sorbinil retinopathy trial indicated that sorbinil had no clinically important effect on the course of human diabetic retinopathy [28].…”

Section: Inhibition Of Increased Polyol Pathwaymentioning

confidence: 99%

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Safi¹,

Qvist²,

Kumar³

et al. 2013

Exp Clin Endocrinol Diabetes

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The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors.

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Section: Inhibition Of Increased Polyol Pathwaymentioning

confidence: 99%

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Safi¹,

Qvist²,

Kumar³

et al. 2013

Exp Clin Endocrinol Diabetes

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“…This is illustrated convincingly by the evidence that nondiabetic animals in which blood hexose concentration is increased with a galactose-rich diet develop retinal capillary lesions that are indistinguishable from those that develop in diabetic humans or animals (1)(2)(3)(4). Multiple hypotheses have proposed how hyperglycemia might cause the development of retinopathy (5)(6)(7)(8)(9)(10)(11), but it has been difficult to recognize which abnormalities are critical.…”

mentioning

confidence: 99%

Abnormalities of Retinal Metabolism in Diabetes and Experimental Galactosemia

2001

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Antioxidants were administered to diabetic rats and experimentally galactosemic rats to evaluate the ability of these agents to inhibit the development of diabetic retinopathy. Alloxan diabetic rats and nondiabetic rats that were fed 30% galactose randomly received standard diets or the diets supplemented with ascorbic acid and ␣-tocopherol (vitamins C؉E diet) or a more comprehensive mixture of antioxidants (multi-antioxidant diet), including Trolox, ␣-tocopherol, N-acetyl cysteine, ascorbic acid, ␤-carotene, and selenium. Diabetes or galactose feeding of at least 12 months resulted in pericyte loss, acellular capillaries, and basement membrane thickening. Compared with diabetic controls, the development of acellular capillaries was inhibited by 50% (P < 0.05) in diabetic rats that received supplemental vitamins C؉E, and the number of pericyte ghosts tended to be reduced. The vitamins C؉E supplement had no beneficial effect in galactosemic rats, but these rats consumed only approximately half as much of the antioxidants as the diabetic rats. The multi-antioxidant diet significantly inhibited (ϳ55-65%) formation of both pericyte ghosts and acellular capillaries in diabetic rats and galactosemic rats (P < 0.05 vs. controls), without affecting the severity of hyperglycemia. Parameters of retinal oxidative stress, protein kinase C activity, and nitric oxides remained elevated for at least 1 year of hyperglycemia, and these abnormalities were normalized by multi-antioxidant therapy. Thus, longterm administration of antioxidants can inhibit the development of the early stages of diabetic retinopathy, and the mechanism by which this action occurs warrants further investigation. Supplementation with antioxidants can offer an achievable and inexpensive adjunct therapy to help inhibit the development of retinopathy in diabetes. Diabetes 50: 1938 -1942, 2001 H yperglycemia induces metabolic disorders that initiate a sequence of events that lead to the development of retinopathy. This is illustrated convincingly by the evidence that nondiabetic animals in which blood hexose concentration is increased with a galactose-rich diet develop retinal capillary lesions that are indistinguishable from those that develop in diabetic humans or animals (1-4). Multiple hypotheses have proposed how hyperglycemia might cause the development of retinopathy (5-11), but it has been difficult to recognize which abnormalities are critical.Diabetes increases oxidative stress in tissues of both humans and animals, and increased oxidative stress might play a role in the development of diabetic complications (8,(12)(13)(14). Oxidative stress develops in the retina of diabetic animals and galactose-fed animals (9,13,15), indicating that oxidative stress is at least associated with the development of retinopathy. Consistent with this, Armstrong et al. (8) reported a correlation between increased serum lipid hydroperoxides and the prevalence of retinopathy in diabetic patients. Our previous studies showed that dietary supplementation with antioxida...

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“…Our study used the same dose of Sulindac as used in the aforementioned study and has shown that in spite of it's aldose reductase inhibitory activity in vitro [11,12], in the diabetic dog this drug did not alter either sorbitol or fructose, the major products of the respective first and second stages of the polyol pathway. There has been considerable interest in the role of the polyol pathyway in the development of galactosaemia-induced retinopathy and diabetic retinopathy however, so far, evidence that inhibition of polyol accumulation prevents the development of retinopathy is conflicting [9,27,28,29,30]. The results of the current study show that inhibition of increased levels of sorbitol is not necessary for the prevention of capillary BM thickening in a long-term model of diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 60%

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

et al. 2003

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Aims/hypothesis. To investigate the effect of treatment with the non-steroidal anti-inflammatory drug Sulindac on the early vascular pathology of diabetic retinopathy in the dog, and it's effect on recognised biochemical indices of hyperglycaemia-related pathophysiology. Methods. Experimental diabetes (streptozotocin/alloxan) was induced in 22 male beagle dogs and 12 of the animals were assigned at random to receive oral Sulindac (10 mg/kg daily). Age-and sex-matched control animals were maintained as non-diabetic controls. After 4 years, several morphological parameters were quantified in the retinal microvasculature of each animal group using an established stereological method. Also, the following diabetes-associated biochemical parameters were analysed: accumulation of advanced glycation end products (AGEs), red blood cell polyol levels and antioxidant status. Results. Diabetes increased red blood cell sorbitol levels when compared to non-diabetic controls (p≤0.05), however, there was no difference in sorbitol levels between the untreated and the treated diabetic animals. No significant differences were found in red blood cell myoinositol levels between the three groups of animals. Pentosidine and other AGEs were increased two-to three-fold in the diabetic animals (p≤0.001) although treatment with Sulindac did not affect their accumulation in diabetic skin collagen or alter diabetesinduced rises in plasma malondialdehyde. Retinal capillary basement membrane volume was significantly increased in the untreated diabetic dogs compared to non-diabetic controls or Sulindac-treated diabetic animals (p≤0.0001). Conclusion/interpretation. This study has confirmed the beneficial effect of a non-steroidal anti-inflammatory drug on the early vascular pathology of diabetic retinopathy. However the treatment benefit was not dependent on inhibition of polyol pathway activity, advanced glycation, or oxidative stress. [Diabetologia (2003[Diabetologia ( ) 46:1269[Diabetologia ( -1275

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Prevention of Retinal Vessel Changes Associated With Diabetic Retinopathy in Galactose-Fed Dogs by Aldose Reductase Inhibitors

Cited by 134 publications

References 15 publications

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

Abnormalities of Retinal Metabolism in Diabetes and Experimental Galactosemia

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug

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