RDR represent a common phenotypic hallmark in GA eyes. RDR are readily identified using cSLO imaging technology. These observations may explain the high prevalence determined herein, in contrast to previous reports based on fundus photographs. Incorporation of these novel imaging modalities in future natural history studies may facilitate efforts aimed at defining the role and predictive value of RDR in the progression of AMD. (ClinicalTrials.gov number, NCT00599846.)

Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (10 mg ⋅ kg −1 ⋅ day −1 ) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: ...

The present study was designed to examine the effect of aldose reductase (AR) overexpression on the development of diabetic neuropathy by using mice transgenic for human AR. At 8 weeks of age, transgenic mice (Tg) and non-transgenic littermates (Lm) were made diabetic with streptozotocin. After 8 weeks of untreated diabetes, plasma glucose levels and the reduction in body weight were similar between the groups of diabetic animals. Despite the comparable levels of hyperglycaemia, levels of sorbitol and fructose were significantly greater in the peripheral nerve of diabetic Tg than in diabetic Lm (both P < 0.01). Ouabain sensitive Na(+),K(+)-ATPase activity was similarly decreased in both diabetic Tg and Lm. Protein kinase C activity in the sciatic nerve membrane fraction was unaffected by diabetes in Lm, but was reduced by nearly 40% in the diabetic Tg. Although both groups of diabetic animals exhibited a significant decrease in tibial nerve motor nerve conduction velocity (MNCV), this decrease was significantly more severe (P < 0.01) in diabetic Tg than in diabetic Lm. Consistent with these findings, nerve fibre atrophy was significantly more severe in diabetic Tg than in diabetic Lm (P < 0.01). These findings implicate increased polyol pathway activity in the pathogenesis of diabetic neuropathy. In support of this hypothesis, treating diabetic Tg with an aldose reductase inhibitor (WAY121-509, 4 mg/kg/day) for 8 weeks significantly prevented the accumulation of sorbitol, the decrease in MNCV and the increased myelinated fibre atrophy in diabetic Tg.

No abstract

Changes in protein kinase (PK) C activity have been implicated in the complications of diabetes mellitus.In retina, blood vessels, kidney and heart, PKC activity is increased [1], perhaps due to raised de novo synthesis of diacylglycerol (DAG). A recent study has shown that PKC inhibitor treatment prevented the development of impaired retinal blood flow, renal glomerular hyperfiltration and microalbuminuria in diabetic rats [2] and this is compatible with the notion that PKC activation contributes to the aetiology of retinopathy and nephropathy.In another complication-prone tissue, peripheral nerve, PKC activity is reduced or unchanged [3±6]. Moreover, one neurochemical explanation of neuro- Diabetologia (1999) AbstractAims//hypothesis. Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151 003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na + ,K + -ATPase, and glutathione deficits in diabetic rats. Methods. Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na + ,K + -ATPase activity were measured in extracts from homogenised sciatic nerves. Results. After 8 weeks of diabetes, sciatic blood flow was 50 % reduced. Two weeks of WAY151 003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20 % diabetic motor conduction deficit, however, at high doses ( > 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na + ,K + -ATPase activity, 42 % reduced by diabetes, was partially corrected by low but not high dose WAY151 003. In contrast, only a very high dose of chelerythrine partially restored Na + ,K + -ATPase activity. A 30 % diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151 003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment. Conclusion/interpretation. Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na + ,K + -ATPase defects. [Diabetologia (1999

These studies suggest that the stimulatory effect of a high level of D(+)-glucose (25 mM) on the expression of the ANG gene in IRPTCs is mediated, at least in part, via the de novo synthesis of DAG, an activator of PKC signal transduction pathway.

These findings demonstrate that the atrophic lesions identified with FAF represent irreversible underlying outer retinal damage. The observation that the width of the atrophic lesion identified with FAF, although significantly correlated but not identical with the width of disruption within the cellular layers of the retina, is consistent with the dynamic nature of the disease. (ClinicalTrials.gov numbers, NCT00393692, NCT00599846.).

Summary Impaired c0-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, highdose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, N%nitro-L-arginine. Eight weeks of diabetes caused an 18.9 % reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg. kg -1. day ~) and WAY121509 (0.2 mg. kg -1. day -t) for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121509 caused marked 71.5 and 82.4 % corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8 % with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121509 (10 rag. kg -1 9 day -1) and primrose oil (10 % dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg. kg -1. day -1) and NG-nitro-Larginine (10 mg. kg -1 9 day -1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived. [Diabetologia (1996) 39: 172-182] Key words Neuropathy, nerve conduction, endoneurial blood flow, ischaemia, essential fatty acid, prostacyclin, aldose reductase, nitric oxide, vascular endothelium, diabetic rat.Impaired nutritive blood flow is the major factor contributing to early peripheral nerve dysfunction in experimental diabetes mellitus [1,2]. This is likely to be relevant to complications in patients, as direct and indirect investigations have provided strong evidence for nerve perfusion deficits associated with diabetic neuropathy [3]. In diabetic rats, neurovascular defects can be prevented or corrected by a number of therapeutic strategies that target the metabolic changes in diabetes or compensate for them by a direct vasodilator action on vasa nervorum [2]. Vascular endothelium appears particularly vulnerable to hyperglycaemia-driven metabolic changes in diabetes. Increased synthesis/action of angiotensin II [4] and endothelin 1 [5] promote vasa nervorum vasoconstriction. This is strongly exacerbated by deficits in prostacyclin synthesis [6] and nitric oxide (NO) release/action [7] which reduce local vasodilation. Prostacyclin changes appear to be caused by defecti...