rhodanine and Body-Weight

Type-2 diabetes mellitus (DM) is associated with cognitive impairment. Increasing evidence establishes that neuro-inflammatory and oxidative stress condition plays a main role in the development of neurodegeneration. Epalrestat, an aldose reductase inhibitor is commonly prescribed for the treatment of diabetic peripheral neuropathy. Its beneficial effects for antioxidant, anti-inflammatory potential and being rhodanine structure containing compound suggests possible role for treatment of DM associated with cognitive dysfunction.. In the present study, we evaluated the effect of epalrestat (54, 27, 13.5 mg/kg, p.o.) and donepezil (1 mg/kg, p.o.) on Tau protein levels, oxidative stress and inflammatory markers in high fat diet (HFD) and Streptozotocin (STZ; 35 mg/kg, i.p.) induced cognitive impairment in diabetic rats.. The epalrestat - 54, 27 mg/kg p.o. and donepezil treatment significantly increased CAT (p < 0.001, p < 0.01, p < 0.001) and GSH (p < 0.001, p < 0.01, p < 0.001) activities respectively as compared to diabetic control rats. In addition, similar dose of epalrestat treatment indicated considerably lowered TAU protein levels (p < 0.001, p < 0.05) while no significant effect was noted with donepezil. These treatments significantly decreased gene expression of TNF-α (1.6, 1.6, 1.7 fold change) and IL-6 (2.5, 1.9, 1.7 fold change). Histopathological examination indicated that epalrestat could attenuate apoptosis of neurons, vacuolations and clumped processes, disorganization and thinning of all the layers.. Our findings suggest that diabetic rats treated with epalrestat could ameliorate the cognition deficits and might act as a beneficial agent for prevention and treatment of cognitive impairment in diabetes.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cognition Disorders; Cytokines; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Diet, High-Fat; Hippocampus; Inflammation; Male; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Rhodanine; tau Proteins; Thiazolidines

We have previously reported the identification of a rhodanine compound (1) with well-balanced inhibitory activity against IKKβ and collagen-induced TNFα activated cells. However, we need more optimized compounds because of its instability over plasma and microsome. As part of a program directed toward the optimization of IKKβ inhibitor, we modified a substituent of parent compound to a series of functional groups. Among substituted compounds, fluorine substituent (12) on the para position of phenyl ring restored the stability toward plasma and microsome while retaining inhibitory potency and selectivity against IKKβ over other kinases. Also, we have demonstrated that compound 12 is an ATP non-competitive inhibitor and safe enough to apply to animal experiment from an acute toxicity test.

Topics: Allosteric Regulation; Animals; Body Weight; Female; Half-Life; Humans; I-kappa B Kinase; Inhibitory Concentration 50; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Protein Binding; Protein Kinase Inhibitors; Rats; Rhodanine

To evaluate the effect of ranirestat, a new aldose reductase inhibitor (ARI), on diabetic retinopathy (DR) in Spontaneously Diabetic Torii (SDT) rats.. The animals were divided into six groups, normal Sprague-Dawley rats (n = 8), untreated SDT rats (n = 9), ranirestat-treated SDT rats (0.1, 1.0, and 10 mg/kg/day, n = 7, 8, and 6, resp.), and epalrestat-treated SDT rats (100 mg/kg/day, n = 7). Treated rats received oral ranirestat or epalrestat once daily for 40 weeks after the onset of diabetes. After the eyes were enucleated, the retinal thickness and the area of stained glial fibrillary acidic protein (GFAP) were measured.. The retinas in the untreated group were significantly thicker than those in the normal and ranirestat-treated (0.1, 1.0, and 10 mg/kg/day) groups. The immunostained area of GFAP in the untreated group was significantly larger than that in the normal and ranirestat-treated (1.0 and 10 mg/kg/day) groups. There were no significant differences between the untreated group and epalrestat-treated group in the retinal thickness and the area of stained GFAP.. Ranirestat reduced the retinal thickness and the area of stained GFAP in SDT rats and might suppress DR and have a neuroprotective effect on diabetic retinas.

Topics: Administration, Oral; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetic Retinopathy; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Glial Fibrillary Acidic Protein; Glycated Hemoglobin; Male; Neuroprotective Agents; Pyrazines; Rats; Rats, Sprague-Dawley; Retina; Rhodanine; Spiro Compounds; Thiazolidines; Time Factors

We examined the effect of fidarestat on the increase in sorbitol content in erythrocytes from healthy volunteers in vitro. Fidarestat inhibited the increase with an IC50 value of 18 nmol/l. A subsequent experiment showed that fidarestat had a similar inhibitory effect on the increase in sorbitol content in erythrocytes from diabetic patients. On the other hand, epalrestat, the only aldose reductase inhibitor used clinically, inhibited increase in sorbitol content at a concentration over 500-fold higher than fidarestat. Although the IC50 value of fidarestat was not affected by fasting plasma glucose, HbA1C, age, aldose reductase content or gender, there was a significant positive relationship between the IC50 value of epalrestat and fasting plasma glucose. In addition, in fidarestat (0.25-2 mg/kg)-treated diabetic rats, the inhibitory rate for erythrocyte sorbitol accumulation was well correlated with that for nerve sorbitol accumulation, which indicates that erythrocyte sorbitol is available for assessing the state of sorbitol pathway flux in target tissue after fidarestat administration. These results suggest that fidarestat potently inhibits the increase in sorbitol pathway flux in diabetic patients independent of various factors and that erythrocyte sorbitol is useful for its estimation.

Topics: Age Factors; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythrocytes; Fasting; Female; Glycated Hemoglobin; Humans; Imidazoles; Imidazolidines; Male; Rats; Rats, Sprague-Dawley; Rhodanine; Sciatic Nerve; Sex Factors; Sorbitol; Thiazolidines

Many patients with diabetes mellitus show a moderate reduction in bone mass. Our recent in vitro studies showed that sustained exposure of osteoblast-like MG-63 cells to high glucose by itself impairs their functions partly via the polyol pathway. To investigate the role of hyperglycemia in the etiology of diabetic osteopenia in vivo separately from insulin deficiency, we determined whether epalrestat, an aldose reductase (AR) inhibitor (ARI), lessens the abnormalities in calcium (Ca) metabolism in galactose-fed rats. Weight gain was impaired in the rats, which was not altered by epalrestat. Galactose feeding temporarily enhanced bone resorption as reflected by increased biochemical markers for bone resorption (urinary excretion of pyridinoline [PYR] and deoxypyridinoline [DPYR]) at 1 to 3 months, which were significantly decreased by epalrestat. Epalrestat also restored the positive correlation between a bone-formation marker (serum osteocalcin [OC]) and a bone-resorption marker (urinary DPYR excretion) at 6.5 months. Histomorphometric analysis of bone performed 6.5 months after galactose feeding showed that both the bone volume and osteoblast numbers in the tibia, which were significantly suppressed by galactose feeding, were partly restored to a significant extent by the simultaneous administration of epalrestat. In summary, epalrestat partially protected against the development of osteoblast dysfunction and reduced the temporary increase in biochemical markers for bone resorption induced by galactose feeding, with a resultant increase in bone volume, suggesting that the polyol pathway may be intimately involved in the development of abnormal bone metabolism in galactose-fed rats.

Topics: Aldehyde Reductase; Amino Acids; Animals; Blood Glucose; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Calcium; Eating; Enzyme Inhibitors; Galactose; Male; Osteocalcin; Polymers; Rats; Rats, Wistar; Rhodanine; Thiazolidines; Tibia

Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied.. Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured.. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat.. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.

Topics: Aldehyde Reductase; Animals; Aorta; Blood Glucose; Body Weight; Coronary Vessels; Diabetic Angiopathies; Dogs; Enzyme Inhibitors; Erythrocytes; Galactitol; Galactose; Glycated Hemoglobin; Male; Polymers; Rhodanine; Thiazolidines

In order to clarify the possible contribution of the abnormal polyol pathway to the development of diabetic nephropathy, the effect of aldose reductase inhibitor on renal function and morphology was examined in streptozotocin (STZ)-induced diabetic rats. Six months after STZ injection, glomerular filtration rate and renal plasma flow showed marked decline with significant increase in nuclear-free mesangial area (MA) and relative mesangial area (RMA; MA per glomerular area) in diabetic rats. Oral administration of an aldose reductase inhibitor, Epalrestat, prevented renal hypofunction and mesangial expansion in diabetic rats without influencing the levels of blood glucose. These results suggest that the abnormal polyol pathway in diabetic rats is closely related to the development of mesangial expansion, a morphologic representative of diabetic glomerulopathy, and renal hypofunction.

Topics: Albuminuria; Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Glomerular Filtration Rate; Glomerular Mesangium; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renal Circulation; Rhodanine; Thiazolidines

1. Isoprenaline and cardiac responsiveness of isolated atria from 2 and 6 week streptozotocin-diabetic rats, and their age-matched controls, was examined. The effects of chronic administration of epalrestat (40 mg/kg orally, by gavage) on diabetes-induced changes were also investigated. 2. Spontaneously beating atria, bathed in either normal or high glucose (30 mmol/L) Krebs' solution, from both 2 and 6 week diabetic rats beat more slowly and with greater force than atria from control rats. These changes in basal parameters were normalized by 2 weeks of insulin (5 U/day s.c.) treatment but not by 2 or 6 weeks of chronic treatment with epalrestat. 3. Isoprenaline (0.1 nmol-0.1 mumol/L) produced concentration-dependent increases in inotropy and chronotropy in atria from both control and diabetic rats. 4. Atria from 2 week diabetic rats displayed decreased sensitivity to the positive inotropic effects of isoprenaline. This change was normalized by chronic insulin treatment but not by chronic epalrestat treatment. 5. Atria from 6 week diabetic rats displayed increased sensitivity to the positive chronotropic effects of isoprenaline which was normalized by epalrestat. 6. These results suggest that changes observed in atria from 2 week diabetic rats may be due to hyperglycaemia per se whereas in atria from 6 week diabetic rats abnormal activity of the polyol pathway may be a contributing factor.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Heart Atria; Heart Rate; In Vitro Techniques; Insulin; Isoproterenol; Male; Myocardial Contraction; Myocardium; Organ Size; Rats; Rats, Wistar; Rhodanine; Thiazolidines

1. To determine the effects of an aldose reductase inhibitor (ARI) on diabetes-induced cardiac sympathetic disturbance, the effects of (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene] rhodamine (ONO-2235), an aldose reductase inhibitor, as well as insulin on the responsiveness to the transmural sympathetic nerve stimulation (TNS) and norepinephrine (NE) of isolated right atria of streptozotocin-induced diabetic rats were investigated. 2. The responsiveness to TNS of 8-week diabetic rats decreased, and those of 12-week diabetic rats severely decreased. The responses to NE also decreased 8 weeks or more after the induction of diabetes. 3. In 8-week diabetic rats, the insulin treatment completely restored the responsiveness to TNS, while ARI treatment partially restored the responsiveness to TNS. In 12-week diabetic rats, the single treatment with insulin or ARI only slightly restored the responsiveness to TNS, while the combination treatment with insulin and ARI almost completely restored the responsiveness to TNS in 12-week diabetic rats. 4. From the present results, the following may be concluded: Sympathetic nerve responses of right atria decreases in diabetic rats, and these changes may be related to hypoinsulinemia and abnormal polyol pathway. Although a serious sympathetic disturbance was only slightly improved by insulin or ARI, the combination of insulin and ARI produced more remarkable improvement of this disturbance.

Topics: Aldehyde Reductase; Animals; Blood Chemical Analysis; Body Weight; Diabetes Mellitus, Experimental; Electric Stimulation; Heart; Heart Diseases; Heart Rate; Insulin; Male; Norepinephrine; Rats; Rats, Inbred Strains; Rhodanine; Sympathetic Nervous System; Thiazolidines

Wistar strain rats were made diabetic by injection of streptozotocin and divided into three groups fed on different diets: conventional solid foods, a fructose-rich diet and a fructose-rich diet mixed with ONO 2235, an aldose reductase inhibitor. The retinas of these rats were examined in flat mount preparations after trypsinization. Microvascular changes such as capillary tortuosity, microaneurysms, pericyte loss, that are typical of diabetic retinal microangiopathy, were seen most frequently in the rats fed on the fructose-rich diet. The rats fed on the fructose-rich diet with ONO 2235 showed much less vascular change than the diabetic rats fed on the conventional food. Electron microscopy of the retina revealed localized thickening of the basement membrane of the retinal capillaries, and this was most frequent in the fructose-fed rats. However, in rats fed on fructose with ONO 2235 the changes of the basement membrane were slight. It was concluded that the aldose reductase inhibitor, ONO 2235, prevented development of diabetic microangiopathy, probably by suppressing the enzymatic activation of aldose reductase in the retina.

Topics: Aldehyde Reductase; Animals; Basement Membrane; Blood Glucose; Body Weight; Capillaries; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Male; Microscopy, Electron; Rats; Rats, Inbred Strains; Retinal Vessels; Rhodanine; Streptozocin; Sugar Alcohol Dehydrogenases; Thiazoles; Thiazolidines

Topics: Animals; Antibodies; Antibody Formation; Binding Sites, Antibody; Body Weight; Cell Membrane Permeability; Cell Migration Inhibition; DNA; Guinea Pigs; Hemagglutination Tests; Horses; Immune Sera; Rhodanine; RNA; Thiazoles