Effect of a potent new aldose reductase inhibitor, (5-(3-thienyl)tetrazol-1-yl)acetic acid (TAT), on diabetic neuropathy in rats

Hotta, Nigishi; Kakuta, Hironobu; Fukasawa, Hideo; Koh, Naoki; Sakakibara, Fumihiko; Nakamura, Jiro; Hamada, Yoji; Wakao, Takaaki; Kara, Thomas; Mori, Kōichi; Naruse, Keiko; Nakashima, Eitaro; Inukai, Shinji; Sakamoto, Nobuo

doi:10.1016/0168-8227(95)01033-a

Cited by 24 publications

(10 citation statements)

References 40 publications

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“…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].…”

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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

et al. 1997

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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: ...

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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

et al. 1997

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“…This effect was accompanied by a reduction in retinal levels of sorbitol and fructose, but not to the level of normal controls, and there was no increase in retinal myo-inositol. Aldose reductase inhibitors reportedly exhibited beneficial effects on the diabetic neuropathy produced by the increased activity of the polyol pathway in diabetes (Gabbay, 1973;Greene & Lattimer, 1982;Gillon, Hawthome & Tomlinson, 1983;Hotta et al 1985;Greene, Lattimer & Sima, 1987;Mizuno et al 1992;Hotta et al 1995). However, the mechanism of action of aldose reductase inhibitors in diabetic neuropathy is not understood.…”

Section: Discussionmentioning

confidence: 99%

“…They had free access to rat chow (CA-1; Clea, Tokyo, Japan) and tap water. Diabetes was induced by the intravenous injection of streptozotocin (60 mg (kg body weight)-'), as described in our previous studies (Hotta, Kakuta, Fukasawa, Kimura, Koh, lida, Terashima, Morimura & Sakamoto, 1985;Hotta, Kakuta, Fukasawa, Koh, Sakakibara, Nakamura, Hamada, Wakao, Hara, Mori, Naruse, Nakashima, Inukai & Sakamoto, 1995). The drug was dissolved in 3 mm citric acid buffer (pH 4.5) prepared immediately before the injection.…”

Section: Animalsmentioning

confidence: 99%

Effect of an aldose reductase inhibitor, SNK‐860, on deficits in the electroretinogram of diabetic rats

Hotta

Koh

Sakakibara

et al. 1995

Experimental Physiology

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SUMMARYTo determine the effect of an aldose reductase inhibitor, SNK-860, on the worsening of the electroretinogram (ERG) during a diabetic state, rats with streptozotocin-induced diabetes were administered SNK-860 (1 or 4 mg kg-' orally) daily for 4 weeks. The effectiveness of SNK-860 in prolonging the peak latencies of oscillatory potentials in the b-wave of the electroretinogram of diabetic rats varied between these different waveform components (designated O1, 02 and 03). SNK-860 (4 mg kg-' day-') either completely or partially prevented the prolonged peak latencies at 01 and (0°1 + 02 + 03). The drug failed to shorten the latency of the 02 and 03 components, and produced only a modest reduction in retinal levels of sorbitol and fructose, with no increase in myo-inositol. There was a significant correlation between the state of the ERG (components 0, and X(01 + 02 + 03)) and the retinal levels of sorbitol and fructose (P < 0.01), but not of myo-inositol.It is concluded that a better understanding of the mechanism by which SNK-860 acts may provide new insight into the pathogenesis of hyperglycaemic retinal dysfunction and help to establish effective therapy for diabetic retinopathy.

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“…Diabetes was induced by the intravenous injection of streptozotocin (60 mg kg-I) [22,23]. The drug was dissolved in 3 mmol L-' citric acid buffer (pH 4.5) immediately before injection.…”

Section: Animalsmentioning

confidence: 99%

“…In the present study, streptozotocin-induced diabetic rats were given a potent aldose reductase inhibitor [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT) [21,22], and the changes in b-wave latency in the ERG as well as the retinal sorbitol content and platelet aggregation were determined to investigate the pathogenesis of diabetic retinopathy and the mechanism of the preventive effect of this drug.…”

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An aldose reductase inhibitor, TAT, prevents electroretinographic abnormalities and ADP‐induced hyperaggregabiIity in streptozotocin‐induced diabetic rats

Hotta¹,

Koh²,

Sakakibara³

et al. 1995

Eur J Clin Investigation

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Rats with streptozotocin-induced diabetes were oral given TAT, a potent aldose reductase inhibitor, at a dose of 10 mg kg-1 day-1 or 40 mg kg-1 day-1 for 30 days. Prolongation of the peak latency of oscillatory potentials in the b-wave of the electroretinogram (ERG), which is associated with retinal Müller cell dysfunction, was significantly improved by treatment with TAT as compared with untreated diabetic rats [sigma(O1 + O2 + O3) was 106.8 +/- 1.8 ms in normal controls (NC), 118.2 +/- 1.1 ms in diabetic controls (DC) (P < 0.001 vs. NC), 110.8 +/- 1.5 ms with 10 mg kg-1 TAT (P < 0.001 vs. DC) and 111.4 +/- 1.6 ms with 40 mg kg-1 TAT (P < 0.01 vs. DC)]. The improvement in ERG abnormalities in diabetic rats was accompanied by partial reduction of elevated sorbitol levels in the retina and erythrocytes, and by correction of platelet hyperaggregability. The authors' findings suggest that a better understanding of the mechanism by which TAT acts may provide new insights into the pathogenesis of hyperglycaemic retinal dysfunction and contribute to establishing effective therapy for diabetic retinopathy.

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Effect of a potent new aldose reductase inhibitor, (5-(3-thienyl)tetrazol-1-yl)acetic acid (TAT), on diabetic neuropathy in rats

Cited by 24 publications

References 40 publications

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

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

Effect of an aldose reductase inhibitor, SNK‐860, on deficits in the electroretinogram of diabetic rats

An aldose reductase inhibitor, TAT, prevents electroretinographic abnormalities and ADP‐induced hyperaggregabiIity in streptozotocin‐induced diabetic rats

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