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PubMed2003

Transgenic mice overexpressing aldose reductase in Schwann cells show more severe nerve conduction velocity deficit and oxidative stress under hyperglycemic stress.

To further understand the role of aldose reductase (AR) in the etiology of diabetic neuropathy, we generated transgenic mice that overexpress AR specifically in the Schwann cells under the control of the rat myelin protein zero (P0) promoter. One of the transgenic mouse lines, which has overexpression of AR mRNA in the Schwann cell only and higher AR activity in the sciatic nerve, was used to examine the relationship between increased AR activity and motor nerve conduction velocity (MNCV) deficit under diabetic and galactosemic conditions. Under these conditions, nontransgenic mice showed a slight reduction in MNCV compared to those of controls. However, transgenic mice exhibited a significantly greater reduction in MNCV under these conditions, particularly under galactosemic condition, indicating that a Schwann cell-specific increase in aldose reductase activity is sufficient to produce the phenotype. Interestingly, under galactosemic condition where the difference in MNCV deficit between transgenic and nontransgenic mice was most pronounced, there was no significant difference in accumulated galactitol levels in the sciatic nerve between these mice. These results indicate that increase in AR activity leads to greater reduction of MNCV under galactosemic and diabetic conditions, but galactitol and sorbitol levels may not be good indicators of the severity of neuropathy. On the other hand, the level of reduced glutathione (GSH) in the sciatic nerve was found to be correlated with the severity of MNCV deficit under the diabetic condition. Diabetic AR transgenic mice showed significant reduction of GSH in their sciatic nerve, whereas the diabetic nontransgenic mice showed no reduction in GSH level compared to the nondiabetic control, suggesting that AR is a key contributor to oxidative stress under diabetic condition.

Aldehyde Reductase↗
PubMedDate not supplied

Effect of SG-210, a novel aldose reductase inhibitor, on impaired polyol pathway in rats received diabetic manipulations.

To investigate the effect of SG-210, a potent inhibitor selective to aldose reductase (ARI), on the impaired polyol pathway, we examined biochemically and histologically the potencies of this compound in streptozotocin-induced diabetic or galactosemic rats. The study with diabetic rats showed that SG-210 (1-10 mg x kg(-1)) dose-dependently inhibited sorbitol accumulations in erythrocytes, sciatic nerves, lens, and retina with ED50 values of 1.4, 1.3, 3.5, and 4.6 mg x kg(-1), respectively. Zenarestat, currently under clinical trials both in Japan and the United States, was about two or over five times less potent than SG-210 in suppressing sorbitol contents of erythrocytes or other tissues, respectively. Epalrestat, commercially available, was much less potent in reducing the contents with ED50 values of more than 30 mg x kg(-1) in all of the cells and the tissues examined. An extensive study using galactosemic rats indicated that SG-210 (3-30 mg x kg(-1)) inhibited galactitol accumulations in lens and retina as well as in erythrocytes, preventing the progression of histological abnormalities in lens accompanied by the reduction in galactitol contents. Epalrestat (3-30 mg x kg(-1)) failed to show any significant effects. Pharmacokinetic studies suggested that SG-210 has a high bioavailability and possesses a long half-life in rats (ca. 10 h). Taken together with its excellent pharmacokinetic profiles, the potent suppressive effects of SG-210 observed in this study may be available as a new treatment of diabetic complications.

Aldehyde Reductase↗
PubMed1995

Assessment of mammary gland metabolism in the sow. II. Cellular metabolites in the mammary secretion and plasma during lactogenesis II.

The concentrations of lactose, glucose, glucose 6-phosphate, glucose 1-phosphate, UDPglucose, UDPgalactose, UDP, UMP, inorganic phosphate, ADP and AMP (metabolites involved in the lactose synthesis pathway), and cAMP, galactose and fructose were measured in the mammary secretion from sucked (n = 9) and unsucked (n = 4) mammary glands of nine sows during the first 5 d post partum. The concentrations of lactose, glucose, galactose and fructose were also measured in plasma during this time. The progressive increase in the concentration of lactose, and changes in the concentrations of cellular metabolites in the mammary secretion from sucked glands were consistent with an increase in the metabolic activity of those glands during lactogenesis II. In contrast, unsucked glands showed a progressive decrease in the concentration of lactose, while the concentrations of cellular metabolites in the milk generally remained unchanged. These results indicated that there was no increase in the metabolic activity of unsucked glands (no increase in lactose synthesis or utilization of glucose and ATP) and that the rate of lactose synthesis prior to milk removal was limited by the availability of glucose and/or UDPgalactose. Therefore, the removal of colostrum from the mammary gland was necessary for an increase in the rate of lactose synthesis (and probably de novo fatty acid synthesis) and implies that autocrine mechanisms are operating to control the rate of milk synthesis during lactogenesis in the sow. The low concentration of glucose in colostrum compared with that in plasma is discussed in view of the paracellular pathway.

Animals↗
PubMed1995

Assessment of mammary gland metabolism in the sow. III. Cellular metabolites in the mammary secretion and plasma following weaning.

The concentrations of lactose, glucose, glucose 6-phosphate, glucose 1-phosphate, UDPglucose, UDPgalactose, UDP, UMP, inorganic phosphate, ADP and AMP (metabolites involved in the lactose synthesis pathway), and cAMP, galactose and sodium were measured in the mammary secretion from four or five mammary glands on each of six sows during the first 5 d post weaning. The concentrations of lactose, glucose and galactose were also measured in plasma during this time. Following weaning, the rapid increase in the concentrations of glucose 6-phosphate and UDPgalactose suggested that the rate of lactose synthesis was regulated by the inhibition of hexokinase and/or lactose synthase, while the decrease in glucose and AMP indicated a subsequent decline in glucose and ATP utilization. The rapid increase in glucose 6-phosphate which plays a pivotal role as a substrate for both lactose and de novo fatty acid synthesis, and the rapid decrease in AMP which reflects ATP utilization, were good markers of decreased metabolic activity. These rapid changes in the metabolic activity of the mammary glands were not observed in a second weaning study when two piglets were removed from selected mammary glands for periods up to 5 h during established lactation. Since concentrations of lactogenic hormones remain elevated following partial weaning, but fall following total weaning (Rojkittikhun et al. 1991), these differences in mammary gland metabolism indicate that endocrine rather than autocrine mechanisms are controlling lactose and fat synthesis during the initial stages of total weaning.

Animals↗
PubMed2004

Free galactose concentrations in fresh and stored apples (Malus domestica) and processed apple products.

Gas chromatography was used to quantitate free galactose in Braeburn, Fuji, Red Delicious, and Spartan apples during cold storage, after thermal processing of apple slices and in juice produced using clarification and/or liquifaction enzymes. Spartan had significantly higher galactose levels as compared to Red Delicious apples, but changes in galactose in all varieties during 9 months of cold storage were insignificant. Blanching and canning decreased galactose levels, but doubling the thermal processing during canning increased the free galactose concentration detected in plant tissue. An enzymatic liquefaction aid used to prepare apple juice dramatically increased the free galactose content while a clarification aid caused only a slight increase due to its selective action on soluble pectin. These findings provide useful information for dietitians to base diet recommendations for galactosemic patients.

Beverages↗
PubMed1999

Cataract development in sand and galactosemic rats fed a natural tomato extract.

This study investigated the effect of a natural tomato extract (TE) on cataract formation in two animal models. A TE containing 5% lycopene was included in the diet of diabetic sand rats at 0.2%, and Sprague Dawley rats were fed a high-galactose diet (30 g/100 g of diet), supplemented with either the lycopene-rich extract at concentrations of 0.2, 0.4, and 0.8% or BHT (0.2%). TE had no significant effect on plasma glucose levels or cataract development in sand rats; however, in rats maintained on a diet rich in galactose, both BHT and TE decreased cataract incidence, and grades were lower than in control animals. In addition, lens protein and reduced glutathione levels were higher and aldose reductase activity was lower than in the control group. The results suggest that antioxidants act as protective agents when oxidative stress is a primary cause of cataract formation but may be less effective in preventing cataracts in hyperglycemic animals.

Analysis of Variance↗
PubMed1994

Novel spirosuccinimide aldose reductase inhibitors derived from isoquinoline-1,3-diones: 2-[(4-bromo-2-fluorophenyl)methyl]-6- fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone and congeners. 1.

The high concentrations of plasma glucose formed during diabetic hyperglycemia rapidly translate into high levels of glucose in tissues where glucose uptake is independent of insulin. In these tissues that include the lens, retina, nerve, and kidney, this excess glucose enters the sorbitol (polyol) pathway. The first enzyme in this pathway, aldose reductase, reduces glucose to sorbitol. The diabetes-induced increased flux of glucose through the polyol pathway is believed to play an important role in the development of certain chronic complications of diabetes mellitus. Compounds that inhibit aldose reductase activity and block the flux of glucose through the polyol pathway prevent the development of neuropathy and nephropathy in diabetic animals and interrupt the progression of neuropathy in diabetic patients. Here we describe the preparation and characterization of novel aldose reductase inhibitors. These spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'-(2H)-tetrones, based on the isoquinoline-1,3-dione framework, were evaluated in vitro for their ability to inhibit glyceraldehyde reduction, using a partially purified bovine lens aldose reductase preparation, and in vivo for their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. Substitution at the N-2 position of the isoquinoline-1,3-dione framework with diverse structural substituents (i.e., aralkyl, benzothiazolylmethyl, methyl) produced several excellent series of ARIs. Optimization of these new series of spirosuccinimides through structure-activity relationship (SAR) studies, including analogy from other drug series (ponalrestat, zopolrestat), led to the design of the clinical candidate 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H ),3'- pyrrolidine]-1,2',3,5'(2H)-tetrone (41). Compound 41 exhibited exceptional oral potency in two animal models of diabetic complications, the 14-day galactose-fed and streptozocin-induced diabetic rats, with ED50 values for the sciatic nerve of 0.1 and 0.09 mg/kg/day, respectively. Both enantiomeric forms of 41 exhibited similar inhibitory activity in both in vitro and in vivo assays possibly due to their rapid interconversion. In an ex vivo experiment, the pharmacodynamic effect of 41 in the plasma of rats and dogs, after a single dose, appeared to be comparable to that of tolrestat.

Aldehyde Reductase↗
PubMed1994

N-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid aldose reductase inhibitors derived from isoquinoline-1,3-diones. 2.

The isoquinoline-1,3-dione framework featured in our clinical candidate (1) and its congener was used as the template in the design of several new series of aldose reductase inhibitors (ARIs). These series included N'-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid analogues. Compounds within these series were evaluated in vitro for their ability to inhibit glyceraldehyde reduction by bovine lens aldose reductase and in vivo by their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. The N'-amino- and N'-alkyl-substituted spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)- tetrones 6 exhibited high oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. Similar results were observed for the closely related spiropyridazines 8. Both of these groups are also considered to be prodrugs since they exhibited good oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. In contrast, the isoquinoline-1,3-dione acetic acids 9 exhibited very high intrinsic activity for the aldose reductase enzyme, although minimal or no in vivo activity. The absence of in vivo activity for some of these compounds may be due to poor tissue penetration. In support of this suggestion, the more lipophilic acetyl alkyl carbamate derivatives of these isoquinoline-1,3-dione acetic acids, exhibited enhanced oral potency. The spiroazetidines 7 exhibited good activity for the aldoe reductase enzyme in both the in vitro and in vivo assays. The findings of this study demonstrate the utility of the isoquinoline-1,3-dione framework, as a versatile template for the design of divese series of potent ARIs.

Acetates↗
PubMed1990

(Pyrimidinyloxy)acetic acids and pyrimidineacetic acids as a novel class of aldose reductase inhibitors.

Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-1-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity.

Acetates↗
PubMed2001

[1,2,4]Triazino[4,3-a]benzimidazole acetic acid derivatives: a new class of selective aldose reductase inhibitors.

Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.

Acetates↗
PubMed2003

Novel, highly potent aldose reductase inhibitors: cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives.

Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent compound 39 exhibited a good inhibitory activity with an IC(50) value of 0.85 microM, similar to that of the well-known ARI sorbinil (IC(50) 0.50 microM). The concurrent introduction of a halogen and a lipophilic group in the 5- and in the 1-positions, respectively, of the indole nucleus of 39, gave compound 55, cyano[5-fluoro-1-(4-methylbenzyl)-2-oxo-2,3-dihydroindol-3-yl]acetic acid, which displayed the highest activity (IC(50) 0.075 microM, very close to that of tolrestat IC(50) 0.046 microM), with a good selectivity toward ALR2 compared with aldehyde reductase (ALR1) (16.4-fold), and no appreciable inhibitory properties against sorbitol dehydrogenase (SD), or glutathione reductase (GR). The isopropyl ester 59, a prodrug of 55, was found to be almost as effective as tolrestat in preventing cataract development in severely galactosemic rats when administered as an eye drop solution. Docking simulation of 55 into a three-dimensional model of human ALR2 made it possible to formulate the hypothesis that the 2-hydroxy tautomer was the active species binding into the catalytic site of the enzyme. This was fully consistent with the structure-activity relationships within this series of cyanooxoindolylacetic acid derivatives.

Acetates↗
PubMed2005

Naphtho[1,2-d]isothiazole acetic acid derivatives as a novel class of selective aldose reductase inhibitors.

Acetic acid derivatives of naphtho[1,2-d]isothiazole (NiT) were synthesized and tested as novel aldose reductase (ALR2) inhibitors. The parent compound 11 exhibited a fair inhibitory activity (IC(50) = 10 muM), which was enhanced by 2 orders of magnitude by introducing a second carboxylic group at position 4 (13 and 14: IC(50) = 0.55 and 0.14 muM, respectively). Substitution of the acetic acid function with an apolar group gave inactive (29) or poorly active (25, 26, 30) compounds, thus demonstrating that the 2-acetic group is involved in the enzyme pharmacophoric recognition while the 4-carboxylic moiety has only an accessory role. The potent compounds 11, 13, 14, 26 all proved to be selective for ALR2, since none of them inhibited aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The isopropyl ester 31, a prodrug of 14, was found to be effective in preventing cataract development in severely galactosemic rats, when administered as an eyedrop solution. The theoretical binding mode of 13 and 14, obtained by docking simulations into the ALR2 crystal structure, was fully consistent with the structure-activity relationships in the NiT series.

Acetates↗
PubMed1997

Biochemical characterization of the S135L allele of galactose-1-phosphate uridylyltransferase associated with galactosaemia.

Impairment of the human enzyme galactose-1-phosphate uridylyltransferase (GALT) results in the potentially lethal disorder galactosaemia. The S135L mutation, which accounts for almost 50% of the GALT alleles in galactosaemia patients of African-American descent, has been associated with activities ranging from null to wild-type by different investigators examining cell lysates representing different tissues or model systems. Because of the crude nature of the lysates examined, however, and the absence of quantitative measures concerning GALT abundance in most of those lysates, the available data do not distinguish between differences in GALT enzyme expression/abundance, specific activity, or kinetic constants in these different tissues or systems. In an effort to overcome this uncertainty and investigate the biochemical impact of the S135L substitution on human GALT function under defined conditions, we have overexpressed both wild-type and S135L-mutant GALT sequences in a null-background yeast expression system, and purified both proteins to near homogeneity. Abundance of the wild-type and mutant proteins in crude yeast lysates differed by approximately 2-fold. Kinetic studies of the purified proteins, however, demonstrated that although K(m) values differed by < 2-fold, specific activities differed by 10-fold. Temperature-activity profiles revealed no significant differences, and coprecipitation studies demonstrated that S135L-hGALT subunits remained competent to self-associate in vivo. We conclude that the S135L substitution causes either steric or electrochemical changes sufficiently close to the active site in human GALT to result in partial impairment of the transferase reaction.

Alleles↗
PubMed1998

Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.

Inherited deficiencies of UDP-galactose 4-epimerase (GALE) have been associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programmes for classical galactosaemia, and are of African-American descent. At least two symptomatic patients have been reported, one Pakistani and the other Asian Muslim, both with severe complications in the neonatal period and subsequent mental retardation. Through newborn screening, we have identified a GALE-deficient patient who is of mixed Pakistani/caucasian ancestry. He was clinically well in the neonatal period on a lactose-containing diet, and biochemical studies, including urine reducing sugars and galactitol, were consistent with a diagnosis of peripheral GALE deficiency. Although early developmental milestones were met normally, he now shows significant developmental delays in both motor and language skills. Mutational analysis revealed this patient to be a compound heterozygote at the GALE locus, with mutations N34S and L183P identified in the patient and confirmed in the parents. This report represents the first characterization of specific mutations in a GALE-deficient patient in conjunction with biochemical and clinical phenotype, and facilitates further studies of the GALE enzyme and its role in the different clinical forms of epimerase-deficiency galactosaemia.

Child, Preschool↗
PubMed1997

A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine.

Existing longitudinal data on patients with classical galactosaemia suggests that neurocognitive functioning is impaired and, in isolated case reports, may show a decline in performance over time. The present study explored whether there are long-term changes in cognitive abilities in patients with galactosaemia and whether oral uridine can improve neurocognitive performance. Thirty-five patients (18 males, 17 females), 29 of whom received oral uridine powder at 150 mg/kg per day (divided dose, three times daily), were evaluated over a 2-5-year period with the Woodcock-Johnson Revised Cognitive Abilities Test, three academic achievement tests, and the Beery Test of Visual Motor Integration. Results showed that the uridine cohort and a comparison group that received only dietary restriction made small gains in cognitive performance over the treatment period and the size of the gains did not differ significantly. Seven subjects who started uridine prior to the age of 14 months did not differ significantly in their cognitive test scores at an average age of 3.5 years from a group of older children who had begun treatment at 4.5 years of age. These results provide no support for any developmental or uridine-treatment-related change in cognitive functioning for this sample of galactosaemic subjects.

Achievement↗