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Aldose Reductase Inhibitor

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Yukio Shigeta – One of the best experts on this subject based on the ideXlab platform.

Boas Gonen – One of the best experts on this subject based on the ideXlab platform.

Nigishi Hotta – One of the best experts on this subject based on the ideXlab platform.

T. C. Hohman – One of the best experts on this subject based on the ideXlab platform.

  • correction of nerve conduction and endoneurial blood flow deficits by the Aldose Reductase Inhibitor tolrestat in diabetic rats
    Journal of The Peripheral Nervous System, 1998
    Co-Authors: Murray A Cotter, Norman E Cameron, T. C. Hohman
    Abstract:

    Increased activation of the first half of the polyol pathway, the conversion of glucose to sorbitol by Aldose Reductase, has been implicated in Aldose Reductase Inhibitor-preventable neurochemical changes that may contribute to the aetiology of diabetic neuropathy. Tolrestat has been used as a standard Aldose Reductase Inhibitor to dissect out polyol pathway-dependent mechanisms in many experimental studies; however, doubt has been cast upon its ability to prevent nerve conduction velocity deficits in diabetic rats. Nerve dysfunction has also been linked to abnormal endoneurial blood flow and oxygenation via increased vasa nervorum polyol pathway flux. The aim of this study was to test whether tolrestat could correct sciatic conduction velocity and perfusion defects in diabetic rats. Sciatic motor conduction velocity, 21% reduced by 1 month of streptozotocin-induced diabetes, was corrected by 23% and 84% with 1 month of tolrestat treatment at doses of 7 and 35 mg/kg/day respectively. Endoneurial blood flow, 44-52% reduced by untreated diabetes, was within the nondiabetic range with high-dose tolrestat treatment and the flow deficit was 39% corrected by the low dose. Sciatic sorbitol and fructose concentrations were approximately 13-fold and approximately 4-fold elevated by untreated diabetes. This was 32-50% attenuated by low-dose tolrestat and sorbitol and fructose content was suppressed below the nondiabetic level by high dose treatment. A 58% nerve myo-inosinositol deficit was partially (32%) corrected by high-dose tolrestat treatment. We conclude that tolrestat restores defective conduction and blood flow in diabetic rats and is a good pharmacological tool for studies on polyol pathway effects in peripheral nerve.

  • effect of hyperglycemia and the Aldose Reductase Inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy
    Journal of Diabetes and Its Complications, 1993
    Co-Authors: Anders A F Sima, T. C. Hohman, Wieslaw J Bochenek, Jay G Graepel, Douglas A. Greene, Morton B. Brown, David Hicks, Boas Gonen
    Abstract:

    Abstract Tolrestat is a well tolerated nonhydantoin Aldose Reductase Inhibitor that has been reported to improve nerve conduction in diabetic animals and humans. Its effects on nerve biochemistry and structure have not been studied in patients with diabetic neuropathy. Patients with advanced diabetic neuropathy treated with long-term open-label tolrestat were randomly assigned to continuation on drug treatment or to placebo-controlled drug withdrawal for 12 months. At the end of this period, sural nerve biopsies were obtained for measurement of glucose, sorbitol, and fructose content, and for detailed morphometric analysis. Tolrestat ameliorated the glucose-mediated increase in sorbitol and fructose in sural nerve tissue. No statistically significant differences in nerve morphometry emerged between the two groups; however, both treatment groups exhibited increased nerve-fiber regeneration and normalization of axo-glial dysjunction and segmental demyelination following long-term tolrestat treatment. These findings are similar to those previously reported in a placebo-controlled sequential nerve biopsy study with the Aldose Reductase Inhibitor sorbinil. Thus tolrestat is a biochemically effective Aldose Reductase Inhibitor in human diabetic nerve with potential therapeutic efficacy for diabetic neuropathy.

  • Intervention with the Aldose Reductase Inhibitor, tolrestat, in renal and retinal lesions of streptozotocin-diabetic rats
    Diabetologia, 1991
    Co-Authors: Michael L Mccaleb, Mar-lee Mckean, T. C. Hohman, Nicholas Laver, W. Gerald Robison
    Abstract:

    The progressive increase in urinary albumin excretion, which precedes the development of diabetic nephropathy, can be prevented in diabetic rats if the Aldose Reductase Inhibitor, tolrestat, is administered at the initiation and throughout the duration of hyperglycaemia. We therefore determined the ability of tolrestat to intervene in the further progression of already established urinary albumin excretion of streptozotocin-diabetic female Wistar rats. Two months after streptozotocin injection, diabetic rats were grouped as low-urinary albumin excretion (0.2–1.0 mg albumin/day) or high-urinary albumin excretion (1.9–5.9 mg albumin/day), at which time tolrestat intervention (25 mg/kg per day) was begun for half of the diabetic rats in each urinary albumin excretion group. After six months of treatment tolrestat caused a significant reduction in the urinary albumin excretion rate of the low-urinary albumin excretion group only. The diabetes-induced rise of total urinary protein in both groups was significantly reduced by tolrestat. Furthermore, the diabetes-induced increase (49%) in the thickness of the basement membranes of retinal capillaries from the outer plexiform layer was significantly diminished by tolrestat administration. In conclusion, intervention therapy with the Aldose Reductase Inhibitor, tolrestat, can reduce the progression of urinary albumin excretion and retinal basement membrane thickening in long-term diabetic rats.

Paul J. Thornalley – One of the best experts on this subject based on the ideXlab platform.

  • modification of the glyoxalase system in streptozotocin induced diabetic rats effect of the Aldose Reductase Inhibitor statil
    Biochemical Pharmacology, 1993
    Co-Authors: Susan A Phillips, Donald Mirrlees, Paul J. Thornalley
    Abstract:

    The glyoxalase system was characterized in tissue (liver, skeletal muscle, kidney cortex and medulla, lens and sciatic nerve) and blood from streptozotocin-induced diabetic rats and normal controls. The effect of the Aldose Reductase Inhibitor, Statil [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazine-1-yl-acetic acid; ICI 128 436], was also investigated. Glyoxalase I and glyoxalase II activities were decreased in the liver and increased in skeletal muscle of diabetic rats and of Statil-treated diabetic rats, relative to normal controls. The concentration of non-protein sulphydryl (NPSH) was decreased in the liver and lens of diabetic rats, relative to normal controls; Statil prevented these effects. The concentrations of methylglyoxal in the kidney cortex and medulla, lens and blood were increased in diabetic rats, relative to normal controls. Statil prevented these increases except in the kidney cortex. The concentration of D-lactate was increased in the lens and blood of diabetic rats, relative to normal controls, which was partially prevented in blood but not in the lens by Statil. These data suggest that the glyoxalase system is modified in tissues and blood of streptozotocin-induced diabetic rats and some of the modifications may be prevented by Statil. The increased concentrations of methylglyoxal in the kidney, lens and blood, and the decreased concentration of NPSH in the lens may be related to the development of diabetic complications.