Treatment with an aldose reductase inhibitor can reduce the susceptibility of fast axonal transport following nerve compression in the streptozotocin-diabetic rat

Summary The effect of treatment with an aldose reductase inhibitor on the susceptibility of peripheral nerves to compression was studied in rats made diabetic by the injection of streptozotocin (50 mg·kg^–1). The response to nerve compression was determined in untreated diabetic rats after 22 days of diabetes and compared with the response in two similar groups of diabetic rats which had been treated with the aldose reductase inhibitor Statil (ICI 128436; 25 mg·kg^–1· day^–1 orally) either from the induction of diabetes or for 7 days prior to nerve compression. Two groups of non-diabetic rats were treated with Statil for either 22 days or 7 days to act as controls. Inhibition of fast axonally transported proteins was induced by local compression of the sciatic nerves 4 h after application of ³H-leucine to the motor neurone cell bodies in the spinal cord. The inhibition of fast axonal transport was quantified by calculation of a transport block ratio.Compression at 30 mmHg for 3 h induced a significantly greater (p<0.05) inhibition of axonal transport at the site of compression in nerves of untreated diabetic rats (transport block ratio 0.96±0.24, n=8) than in nerves of control rats treated with the aldose reductase inhibitor for either the shorter time of 7 days (0.71±0.17, n=10) or the longer time of 22 days (0.69±0.08, n=5). In diabetic rats treated with the aldose reductase inhibitor for 22 days the inhibition (0.77±0.12, n=6) was significantly less than that in untreated diabetic rats; treatment for 7 days reduced the transport block ratio to 0.85±0.11 (n=8), but the effect was not significant. Treatment for 22 days prevented the marked increase in nerve sorbitol found in the diabetic rats but did not prevent a fall in nerve myo-inositol. The results indicate that treatment with an aldose reductase inhibitor for a sufficient period of time can reduce the increased susceptibility of peripheral nerves to compression in streptozotocin-induced diabetes mellitus in the rat by a mechanism which may be related to the prevention of increases in sorbitol in the nerves.     

Inhibition effects of quinones on aldose reductase: Antidiabetic properties

Diabetes mellitus is a chronic metabolic disease characterized by abnormal glucose metabolism. Aldose reductase (AR) is the first enzyme in the polyol pathway and converts glucose to sorbitol. It plays a vital role as a glucose reducing agent and is involved in the pathophysiology of diabetic complications. In this study, we purified AR from sheep kidney with a specific activity of 2.00 EU/mg protein and 133.33- fold purification After the purification of the AR enzyme, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed and the molecular weight of the enzyme was found approximately as 38 kDa. The inhibition effects of eight quinones were studied against AR. The quinones were potent inhibitors of AR with K_i values in the range of 0.07–20.04 μM. Anthraquinone showed the best potential inhibitory effects against AR. All compounds exhibited noncompetitive inhibition against AR. These compounds may be selective inhibitors of this enzyme. AR inhibition is an essential strategy for the attenuation and prevention of diabetic complications.     

Effects of aldose reductase inhibitor and vitamin B12 on myocardial uptake of iodine-123 metaiodobenzylguanidine in patients with non-insulin-dependent diabetes mellitus

This study was undertaken to examine the effects of aldose reductase inhibitor (ARI) and vitamin B₁₂ (VB12) on myocardial uptake of iodine-123 metaiodobenzylguanidine (MIBG) in patients with diabetic autonomic disorder. Myocardial scintigraphy using ¹²³I-MIBG was performed on 20 healthy volunteers (controls) and 56 patients with non-insulin-dependent diabetes mellitus (NIDDM), in order to obtain the heart/mediastinum ratio in the initial (HMi) and the delayed images (HMd), and the washout rate (%WR). Thirty-four of the 56 NIDDM patients could be diagnosed as having diabetic autonomic disorder by evaluating their scintigraphic findings in comparison with the controls. Seventeen of these 34 patients received 150 mg/day of epalrestat (ARI group) in three divided doses before meals, and the other 17 received 1.5 mg/day of mecobalamin (VB12 group) in three divided doses after meals, for 3–5 months. According to the presence or absence of clinical symptoms of autonomic or peripheral somatic nerve disorder, the patients were subclassified into four groups. group 1=patients, with autonomic symptoms or somatosensory disorder in the ARI group; group 2=patients without autonomic symptoms or somatosensory disorder in the ARI group; group 3=patients with autonomic symptoms or somatosensory disorder in the VB12 group; and group 4=patients without autonomic symptoms or somatosensory disorder in the VB12 group. After completion of the treatment, myocardial scintigraphy was performed again. Comparing the results obtained before and after the treatment, it was seen that ARI improved only the HMi in group 1 (P=0.046), whereas VB12 significantly improved HMi in the group 3 (P=0.018) and HMi, HMd and %WR in group 4 (P=0.043, P=0.018 and P=0.043, respectively). We conclude that VB12 is more efficacious than ARI in the treatment of diabetic cardiovascular autonomic disorder. Received 16 May and in revised form 30 July 1998     

黄花远志根化学成分的分离和结构鉴定

从黄花远志(Polygala arilata Buch-Ham.)根中分离得到7个化合物,根据光谱(UV,IR,MS,¹HNMR,DIFNOE和¹³CNMR)解析和理化性质,分别鉴定为1-甲氧基-2,3-亚甲二氧基口山酮(I)、1,7-二羟基-2,3-亚甲二氧基口山酮(II)、1,6,7-三羟基-2,3-二甲氧基口山酮(II)、对羟基苯甲酸(IV)、远志醇(V)、豆甾醇(VI)、豆甾醇β-D-吡喃葡萄糖甙(VII)。其中,I和II为新化合物,VI和VI为首次从该植物中分得。化合物I～II有抑制醛糖酶的作用。     

Effects of Glucose and SNK-860, an Aldose Reductase Inhibitor,on the Polyol Pathway and Chemiluminescence Response of Human Neutrophils in vitro

An in vitro incubation study was conducted to investigate whether increased activity of the polyol pathway in human neutrophils under diabetic conditions resulted in a decrease of superoxide anion produced by NADPH oxidase on the membrane of neutrophils. Lucigenin-enhanced chemiluminescence (CL) to phorbol myristate acetate as respiratory burst and sorbitol levels in neutrophils after incubation with glucose and an aldose reductase (AR) inhibitor, SNK-860 (SNK) were measured. Sorbitol levels increased from 0.210 ± 0.029 nmol 10⁷ cells ^?1 in 5 mmol I^?1 glucose to 0.446 ± 0.036 nmol 10⁷ cells^?1 in 40 mmol I^?1 glucose, while CL decreased from 0.542 ± 0.034 cpm cell^?1 in 5 mmol I^?1 glucose to 0.430 ± 0.018 cpm cell^?1 in 40 mmol I^?1 glucose. The addition of 10 μmol I^?1 SNK normalized the increased sorbitol levels in neutrophils exposed to 40 mmol I^?1 glucose and improved, but did not normalize, the decrease in CL induced by 40 mmol I^?1 glucose (p < 0.001). Galactose (40 mmol I^?1) also reduced CL, which was improved by the addition of SNK (p < 0.01). These results suggest that impaired respiratory burst induced by high-glucose concentrations is caused by competition for NADPH resulting from increased polyol pathway activity and/or glycation and that an AR inhibitor may be capable in part of preventing increased susceptibility to infection in diabetic patients.     

An enzyme kinetics program for desk-top computers

A basic computer program has been developed which will compute statistical parameters on initial velocity data, compute and plot mean initial velocities and 95% confidence limits in all graphical transformed spaces, calculate K_m and V_max values by weighted non-linear regression to a 1:1 rational polynomial function, and plot residual scatter and Hill plot slope from the data input. Plots and calculations for temperature dependence and reversible and irreversible inhibition can also be obtained. The program is suitable for any desk-top microcomputer.     

Aldose reductase pathway contributes to vulnerability of aging myocardium to ischemic injury

Aging men and women display both increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We hypothesized that altered glucose metabolism, in particular, flux of glucose via the polyol pathway (PP) may be responsible, in part, for the enhanced vulnerability of aging myocardium to ischemic injury, even in the absence of superimposed disease processes linked to PP flux, such as diabetes. To test our hypothesis, we determined the expression and products of PP enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in hearts from Fischer 344 aged (26 months) and young (4 months) rats subjected to global ischemia followed by reperfusion in the presence or absence of blockers of PP and the measures of ischemic injury and functional recovery were determined. Expression and activities of AR and SDH were significantly higher in aged vs. young hearts, and induction of ischemia further increased AR and SDH activity in the aged hearts. Myocardial ischemic injury was significantly greater in aged vs. young hearts, and blockade of AR reduced ischemic injury and improved cardiac functional recovery on reperfusion in aged hearts. These data indicate that innate increases in activity of the PP enzymes augment myocardial vulnerability to I/R injury in aging, and that blockers of PP protect the vulnerable aging hearts.     

Polyol pathway and diabetic nephropathy revisited: Early tubular cell changes and glomerulopathy in diabetic mice overexpressing human aldose reductase

Aims/Introduction: The polyol pathway has long been involved in the pathogenesis of diabetic nephropathy. It remains still unclear, however, how the polyol pathway is implicated in this process. We explored the effects of the enhanced polyol pathway on renocortical tubular cells and glomeruli in experimentally‐induced diabetes. Materials and Methods: Transgenic mice (Tg) overexpressing human aldose reductase were made diabetic by streptozotocin and followed for 8 weeks. Renocortical pathology, expressions of tonicity‐responsive enhancer binding protein (TonEBP) and carboxymethyllysine of advanced glycation end‐products, were examined. Wild‐type non‐transgenic mice (Wt) were also made diabetic and served as controls. Results: Diabetic Tg showed augmented expression of TonEBP in renocortical tubular cells with vacuolated degenerative changes. These structural changes were associated with pronounced deposition of carboxymethyllysine. There was a significant increase in kidney weight, glomerular size, and mesangial area in diabetic animals and there was a trend for more severe changes in these measures in diabetic transgenic mice compared with those in control diabetic mice. Treatment with aldose reductase inhibitor significantly prevented polyol accumulation, mesangial expansion and expressions of TonEBP and carboxymethyllysine in diabetic Tg, but its effects on the renal structure were equivocal in control diabetic Wt. Conclusions: Our findings suggest that tubuloglomerular change might contribute to early diabetic nephropathy under the influence of the enhanced polyol pathway. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00071.x , 2010)