The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats

Yue, DK; Hanwell, Michelle A.; Satchell, Paul; Handelsman, David J.; Turtle, John R.

doi:10.1016/0026-0495(84)90097-0

Cited by 28 publications

(13 citation statements)

References 20 publications

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“…The administration of the AR inhibitor M79,175 (Eisai, Japan) completely prevented these changes from occurring. The effect of AR inhibitor on restoring nerve MI level in galactosemic animal is consistent with the previous findings by Yue et al (1984).…”

Section: Galactitol and MI In Galactosemic Rat Nervesupporting

confidence: 92%

“…Another important established fact is that the depletion of MI is related to polyol formation. An inverse relationship has been shown to exist be-tween the gain in polyol and loss in MI in various diabetic and galactosemic tissues (Stewart et al, 1969;Finegold et al, 1983;Yue et al, 1984;MacGregor et al, 1986). Treatment with inhibitors of aldose reductase (AR), the enzyme responsible for polyol synthesis, prevents the MI loss, sorbitol gain, and nerve conduction deficits (Yue et al, 1982;Gillon and Hawthorne, 1983).…”

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confidence: 99%

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Depletion of myo‐Inositol and Amino Acids in Galactosemic Neuropathy

Nishimura

Lou

Kinoshita

1987

Journal of Neurochemistry

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A depletion of not only myo-inositol (MI) but also taurine and other amino acids was observed in the sciatic nerve of a galactosemic rat. Treatment of the galactosemic rats with sorbinil, an aldose reductase (AR) inhibitor, was found to block galactitol formation and protect against the loss of MI, taurine, and other amino acids. Incubation studies of sciatic nerve have revealed that [3H]MI and [3H]taurine were actively taken up and concentrated. Incubation of the nerve in a high-galactose medium showed a decrease in the accumulation of [3H]MI and [3H]taurine whereas the galactitol level increased. Time-course studies have shown that the galactitol level reached a plateau before a substantial decrease in the accumulation of [3H]MI and [3H]taurine occurred. The addition of AR inhibitors in the galactose medium significantly protected against the loss in the capacity of the nerve to accumulate [3H]MI and [3H]taurine. Hypertonicity of the galactose medium also seemed to have a protective effect similar to that of AR inhibitors.

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Section: Galactitol and MI In Galactosemic Rat Nervesupporting

confidence: 92%

mentioning

confidence: 99%

Depletion of myo‐Inositol and Amino Acids in Galactosemic Neuropathy

Nishimura

Lou

Kinoshita

1987

Journal of Neurochemistry

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“…However, in rat and rabbit sciatic nerve there is conflicting evidence for and against an increased nerve water content [5,6,25,26]. Nor in our own experiments have we been able to observe reduced nerve myo-inositol [2] despite other reports of reductions in myo-inositol in both diabetic and galactosaemic rat nerve [6,20], and the argument that changes in myo-inositol underlie the development of neuropathy and its prevention by inhibitors of aldose reductase [27] in experimental diabetes. It is likely that reduced nerve blood flow and the ensuing, or associated endoneurial hypoxia in both the galactose-fed animal and the streptozotocin-diabetic rat [21][22][23] are amplified in the presence of applied mild pressure, which also impairs nerve blood flow, to the extent that the oxygen-dependent fast axonal transport is inhibited [28,29].…”

Section: Discussionmentioning

confidence: 52%

“…The values quoted above in the nerves of rabbits used for measurements of fast transport rate were typical of the values found throughout; the fact that galactitol and myo-inositol levels were low in the experiments involving nerve compression in the absence of Statii was almost certainly a consequence of the fact that it was necessary to measure galactitol and myo-inositol in the same nerves which had been freeze-dried for measurement of nerve water content and then re-constituted. This also led to a loss of myo-inositol even in nerves from control animals [20].…”

Section: Discussionmentioning

confidence: 98%

Pressure-induced inhibition of fast axonal transport of proteins in the rabbit vagus nerve in galactose neuropathy: prevention by an aldose reductase inhibitor

McLean

1988

Diabetologia

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Summary. Fast and slow anterograde axonal transport and retrograde axonal transport of proteins were studied in the mainly non-myelinated sensory fibres of the vagus nerve of rabbits fed a diet of 50% galactose over a period of 29 days. Galactose feeding had no effect on the rate or protein composition of slow transport nor on the amount of retrogradely transported proteins. There was a slight retardation of fast transported proteins although their composition was unchanged. The galactose feeding led to a significant increase (p < 0.005) in nerve water content and nerve galactitol but no significant change in myo-inositol. When 20 mm Hg pressure was applied locally to the cervical vagus nerve, fast transported proteins accumulated proximal to the compression zone in the galactose-fed but not in control rabbits. Administration of the aldose reductase inhibitor Statil (ICI 128436) throughout the experiment prevented the increased susceptibility to pressure and the increase in nerve galactitol and water content. The effects of pressure are similar to those found in the streptozotocin-diabetic rat although the underlying mechanisms may differ.

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“…Recently, the validity of galactose intoxication as a model of diabetic neuropathy has been questioned (18). Galactosemic rats develop deficiencies in slow, retrograde, and turnaround axonal transport (28,54); decreased nerve conduction velocities (55); diminished myo-inositol levels in nerve (18,56); and decreased nerve blood flow (57), as do STZ-D rats. However, diabetic and galactosemic models differ considerably in nerve water content (18), histologic evidence of edema (58), fructose levels (18), and Na + -K + -ATPase activity (42), which is increased in galactosemic nerve.…”

Section: Discussionmentioning

confidence: 99%

Effects of Aldose Reductase Inhibitor Sorbinil on Neuroaxonal Dystrophy and Levels of myo-inositol and Sorbitol in Sympathetic Autonomic Ganglia of Streptozocin-Induced Diabetic Rats

et al. 1989

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Biochemical and ultrastructural effects of the aldose reductase inhibitor sorbinil were examined in two experimental rat models of chronic diabetic neuropathy: rats with streptozocin-induced diabetes (STZ-D) and rats fed a galactose-enriched diet. The frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic ganglia of rats with untreated 8-mo STZ-D increased sevenfold compared with that in age-matched controls. Animals chronically maintained on a diet containing 50% galactose, however, did not develop neuroaxonal dystrophy in excess of that found in untreated age-matched control rats. Institution of sorbinil therapy at the time of induction of STZ-D decreased, but did not completely normalize, the frequency of neuroaxonal dystrophy without altering the severity of diabetes; this finding is based on measurements of plasma glucose, body weight, food consumption, 24-h urine volume, and levels of glycosylated hemoglobin. Sorbitol levels in the superior cervical sympathetic ganglia (SCG) of untreated 8-mo-diabetic animals increased three- to fourfold compared with levels in controls. The increase in sorbitol content of diabetic SCG was completely prevented by early institution of dietary sorbinil therapy. The myo-inositol content of 8-mo-diabetic SCG was modestly decreased compared with controls. Sorbinil administration improved but did not completely normalize diabetic SCG myo-inositol. The sorbitol content of the SCG, superior mesenteric and celiac sympathetic ganglia, and a major trunk of the superior mesenteric nerve of short-term (2.5-mo)-diabetic rats increased comparably, but only the diabetic SCG showed a decrease in myo-inositol.

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The effects of aldose reductase inhibition on nerve sorbitol and myoinositol concentrations in diabetic and galactosemic rats

Cited by 28 publications

References 20 publications

Depletion of myo‐Inositol and Amino Acids in Galactosemic Neuropathy

Depletion of myo‐Inositol and Amino Acids in Galactosemic Neuropathy

Pressure-induced inhibition of fast axonal transport of proteins in the rabbit vagus nerve in galactose neuropathy: prevention by an aldose reductase inhibitor

Effects of Aldose Reductase Inhibitor Sorbinil on Neuroaxonal Dystrophy and Levels of myo-inositol and Sorbitol in Sympathetic Autonomic Ganglia of Streptozocin-Induced Diabetic Rats

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