sorbinil and Disease-Models--Animal

Diabetes mellitus has an effect on many organ systems including the eye, kidney and peripheral nerve. Many of these complications develop in animal models of diabetes, which has allowed some of the mechanisms of damage in target organs to be studied. Aldose reductase, an intracellular enzyme, converts glucose to sorbitol, and it is the intracellular accumulation of sorbitol which is thought to result in irreversible damage. In the diabetic eye the increased sorbitol accumulation in both the lens and the retina has been implicated in the pathogenesis of cataract and retinopathy, the major ocular complications of diabetes. In those experimental models which demonstrate characteristic diabetic complications, pharmacological inhibition of the enzyme aldose reductase has resulted in prevention of target organ damage. This paper summarises the experimental evidence upon which the clinical trials of aldose reductase inhibitors in diabetic patients have been initiated and the results of published drug trials in these patients.

Topics: Aldehyde Reductase; Animals; Cataract; Clinical Trials as Topic; Corneal Diseases; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Phthalazines; Rats; Retinal Vessels

Topics: Aldehyde Reductase; Animals; Binding Sites; Blood Glucose; Cataract; Chemical Phenomena; Chemistry; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Fluorenes; Galactose; Humans; Hydantoins; Imidazoles; Imidazolidines; Models, Molecular; Naphthalenes; Phthalazines; Rhodanine; Sorbitol; Structure-Activity Relationship; Substrate Specificity; Sugar Alcohol Dehydrogenases; Thiazolidines; Tissue Distribution

Tissues of the eye affected by diabetes are the lens, cornea, and retina. The lens becomes cataractous through osmotic swelling of its cortical fibers. Sorbitol, formed in the presence of aldose reductase, accumulates in the lens during hyperglycemia. Dulcitol similarly accumulates in the presence of galactosemia. Cataractogenesis in both cases can be prevented by inhibitors of aldose reductase. The efficacy of synthetic inhibitors differs in various tissues and species, but they react with aldose reductase at a common structural site. The most promising inhibitor is sorbinil . Diabetic retinopathy is similarly related to sorbitol accumulation and may be prevented or reversed by inhibition of aldose reductase. Healing of corneal wounds in diabetes is facilitated by enzyme inhibition. Retinal vasculopathy of diabetes is due to selective loss of the intramural pericytes that normally form structural elements in the retinal capillary walls. The vulnerability of these cells is due to their aldose reductase content. Whether inhibition of aldose reductase will prevent retinopathy is being tested in a randomized trial conducted by the National Eye Institute.

Topics: Aldehyde Reductase; Animals; Axonal Transport; Cataract; Corneal Diseases; Diabetic Neuropathies; Diabetic Retinopathy; Disease Models, Animal; Galactosemias; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Osmolar Concentration; Peripheral Nerves; Rats; Sorbitol; Structure-Activity Relationship; Sugar Alcohol Dehydrogenases

Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual axis leading to visual disability. This postsurgical complication, known as posterior capsular opacification (PCO), occurs in up to 30% of cataract patients and has no clinically proven pharmacological means of prevention. Despite the availability of many compounds capable of preventing early steps in PCO development, there is currently no effective means to deliver such therapies into the eye for a suitable duration. To model a solution to this unmet medical need, we fabricated acrylic substrates as intraocular lens (IOL) mimics scaled to place into the capsular bag of the mouse lens following a mock-cataract surgery. Substrates were coated with a hydrophilic crosslinked acrylate nanogel designed to elute Sorbinil, an aldose reductase inhibitor previously shown to suppress PCO. Insertion of the Sorbinil-eluting device into the lens capsule at the time of cataract surgery resulted in substantial prevention of cellular changes associated with PCO development. This model demonstrates that a cataract inhibitor can be delivered into the postsurgical lens capsule at therapeutic levels.

Topics: Actins; Animals; Cadherins; Capsule Opacification; Cataract; Cataract Extraction; Disease Models, Animal; Drug Carriers; Enzyme Inhibitors; Fibronectins; Gene Expression Regulation; Humans; Imidazolidines; Lens, Crystalline; Lenses, Intraocular; Mice; Nanogels; Signal Transduction; Vimentin

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13-15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (

Topics: Aldehyde Reductase; Amino Acids; Animals; Benzopyrans; Blood Glucose; Catalytic Domain; Cataract; Diabetes Complications; Disease Models, Animal; Drug Design; Enzyme Activation; Enzyme Inhibitors; Imidazoles; Inhibitory Concentration 50; Molecular Docking Simulation; Rats; Stereoisomerism; Structure-Activity Relationship

Retinal microglia become activated in diabetes and produce pro-inflammatory molecules associated with changes in retinal vasculature and increased apoptosis of retinal neurons and glial cells. We sought to determine if the action of aldose reductase (AR), an enzyme linked to the pathogenesis of diabetic retinopathy, contributes to activation of microglial cells.. Involvement of AR in the activation process was studied using primary cultures of retinal microglia (RMG) isolated from wild-type and AR-null mice, or in mouse macrophage cultures treated with either AR inhibitors or small interfering RNA (siRNA) directed to AR. Inflammatory cytokines were measured by ELISA. Cell migration was measured using a transwell assay. Gelatin zymography was used to detect active matrix metalloproteinase (MMP)-9, while RMG-induced apoptosis of adult retinal pigment epithelium (ARPE-19) cells was studied in a cell coculture system.. Aldose reductase inhibition or genetic deficiency substantially reduced lipopolysacharide (LPS)-induced cytokine secretion from macrophages and RMG. Aldose reductase inhibition or deficiency also reduced the activation of MMP-9 and attenuated LPS-induced cell migration. Additionally, blockade of AR by sorbinil or through genetic means caused a reduction in the ability of activated RMG to induce apoptosis of ARPE-19 cells.. These results demonstrate that the action of AR contributes to the activation of RMG. Inhibition of AR may be a therapeutic strategy to reduce inflammation associated with activation of RMG in disease.

Topics: Aldehyde Reductase; Analysis of Variance; Animals; Apoptosis; Blotting, Western; Cell Movement; Cells, Cultured; Cytokines; Disease Models, Animal; Endotoxins; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Imidazolidines; Macrophages; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Microglia; Retina; Retinal Diseases

The acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as selective aldose reductase (ALR2) inhibitors. Compound PS11 showed highest inhibitory activity (IC(50)) 0.32 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.

Topics: Acetic Acid; Aldehyde Reductase; Animals; Benzimidazoles; Cataract; Disease Models, Animal; Enzyme Inhibitors; Galactosemias; Inhibitory Concentration 50; Molecular Structure; Naphthalenes; Ophthalmic Solutions; Rats

Increased production of cytokines and chemokines in serum and tissues upon oxidative stress caused by severe systemic infections are the major cause of sepsis. Aldose reductase (AR) known to mediate oxidative stress-induced NF-kappaB activation and transcription of cytokines and chemokines are the main mediator of bacterial endotoxin-induced inflammatory response. Our aim is to investigate the effect of AR inhibitors on the prevention of inflammatory cytokines in the cecum ligation and puncture (CLP) model of polymicrobial sepsis which closely mimics the sepsis syndrome in humans.. Mice were rendered septic by CLP in the absence and presence of AR inhibitor, sorbinil. The levels of cytokines, chemokines and other inflammatory markers in the plasma, peritoneal fluid and heart of mice were significantly inhibited by sorbinil. Inhibition of AR also prevented CLP-induced COX-2, iNOS and HMGB-1 in heart, kidney and spleen.. Our results showed that the inhibition of AR significantly prevented the polymicrobial sepsis-induced increase in inflammatory markers and thus indicate the use of AR inhibitors as anti-inflammatory agents.

Topics: Aldehyde Reductase; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Imidazolidines; Mice; Mice, Inbred BALB C; Systemic Inflammatory Response Syndrome

Naphthalene-induced cataract in rat lenses can be completely prevented by AL01576, an aldose reductase inhibitor (ARI). In an attempt to understand the mechanism of this inhibition, several ARIs were examined to compare their efficacies in preventing naphthalene cataract, using both in vitro and in vivo models. Two classes of ARIs were tested: One group including AL01576, AL04114 (a AL01576 analog) and Sorbinil contained the spirohydantoin group, while Tolrestat contained a carboxylic acid group. Furthermore, to clarify if aldose reductase played a role in naphthalene-induced cataractogenesis in addition to its role in sugar cataract formation, a new dual cataract model was established for ARI evaluations. This was achieved by feeding rats simultaneously with high galactose and naphthalene or incubating rat lenses in culture media containing high galactose and naphthalene dihydrodiol. Under these conditions, both cortical cataract and perinuclear cataract developed in the same lens. It was found that at the same dosage of 10 mg/kg/day, both AL01576 and AL04114 completely prevented all morphological and biochemical changes in the lenses of naphthalene-fed rats. Sorbinil was less efficacious, while Tolrestat was inactive. AL01576 showed a dose-response effect in preventing naphthalene cataract and at 10 mg/kg/day, it was also effective as an intervention agent after cataractogenesis had begun. With the dual cataract model, Tolrestat prevented the high galactose-induced cortical cataract but showed no protection against the naphthalene-induced perinuclear cataract. AL01576, on the other hand, prevented both cataract formations. Results for dulcitol and glutathione levels were in good agreement with the morphological findings. AL04114, and ARI as potent as AL01576 but without its property for cytochrome P-450 inhibition, displayed similar efficacy in preventing naphthalene cataract. Based on these results, it was concluded that the prevention of the naphthalene cataract probably results from inhibition of the conversion of naphthalene dihydrodiol to 1,2-dihydroxynaphthalene and that the effect of the ARIs cannot be explained by their inhibition of the dihydrodiol dehydrogenase activity of aldose reductase.

Topics: Aldehyde Reductase; Animals; Cataract; Culture Techniques; Disease Models, Animal; Enzyme Inhibitors; Fluorenes; Galactose; Hydantoins; Imidazoles; Imidazolidines; Male; Naphthalenes; Rats; Spiro Compounds

To determine if the retinal microangiopathies of the galactose-fed rat model of diabetic retinopathy can be prevented with the aldose reductase inhibitor sorbinil.. Sprague-Dawley rats were fed 50% d-galactose with or without sorbinil (0.05% wt/wt), mixed biweekly with fresh diet. Rats in each group were examined frequently by slit lamp and were killed after 8, 16, and 24 months. Computer-assisted morphometry was performed on wholemounts of elastase retinal digest preparations.. Cataracts developed in all galactose-fed untreated rats within 3 weeks but not in the sorbinil-treated rats even after 24 months. At 8 months, the galactose-fed untreated rats exhibited statistically significant increases in the mean capillary width, the percent of retinal area occupied by capillaries (capillary density), and the percent of microvascular area with capillaries > 20 microns wide (dilated channels), compared to controls. At 16 months, the galactose-fed untreated rats showed statistically significant increases over controls in both total mean capillary length and density, and two of the four rats examined had microaneurysms. At 24 months, all the galactose-fed untreated rats had microaneurysms and extensive areas with hypercellular meshworks composed of dilated channels characteristic of intraretinal microvascular abnormalities (IRMA). By contrast, galactose-fed, sorbinil-treated rats, at 24 months, had no IRMA and showed no statistically significant differences from control rats in any of the parameters measured morphometrically.. All the galactose-induced retinal microangiopathies were prevented with sorbinil. Aldose reductase inhibitors may be beneficial in ameliorating the similar vascular lesions characteristic of human diabetic retinopathy, though the mechanism remains obscure.

Topics: Aldehyde Reductase; Animals; Capillaries; Cataract; Diabetic Retinopathy; Disease Models, Animal; Enzyme Inhibitors; Galactose; Image Processing, Computer-Assisted; Imidazoles; Imidazolidines; Male; Rats; Rats, Sprague-Dawley; Retinal Vessels

The suitability of the galactose-fed rat as a model of diabetic retinopathy was examined in nondiabetic rats fed diets enriched with either 30% or 50% galactose for up to 2 years.. Retinal capillaries were examined by light and electron microscopy, and the prevalence or severity of diabetic-like lesions was quantitated.. Histologic evaluation of trypsin digests of retina revealed significantly greater than normal frequencies of pericyte ghosts and acellular capillaries at both 15 and 23 months receiving a 50% galactose diet. Similar lesions were observed in rats receiving a 30% galactose diet for 23 months. Capillary basement membrane thickening, dilated hypercellular capillaries (or intra-retinal microvascular abnormalities), and foci of vascular cells appeared in rats fed 50% galactose, but saccular microaneurysms characteristic of retinopathy in diabetic patients, diabetic dogs, and experimentally galactosemic dogs were not observed. Administration of the aldose reductase inhibitor, Sorbinil, to rats fed 50% galactose resulted in a significant inhibition of cataract and of galactitol accumulation in nerve and blood (by more that 90%) and retina (by 62%), but did not inhibit development of the retinal microvascular lesions.. Two years of galactosemia in rats seems to reproduce only a portion of the lesions characteristic of diabetic retinopathy in patients or dogs. Nevertheless, lesions characteristic of at least the early stages of retinopathy clearly do develop in this galactosemic rat model, and are not restrained by inhibition of retinal polyol accumulation by 62%.

Topics: Aldehyde Reductase; Animals; Basement Membrane; Capillaries; Cataract; Diabetic Retinopathy; Disease Models, Animal; Erythrocytes; Galactitol; Galactose; Galactosemias; Imidazoles; Imidazolidines; Male; Rats; Rats, Sprague-Dawley; Retina; Retinal Vessels; Sciatic Nerve

Galactitol and myo-inositol concentrations were measured in retinas, erythrocytes, and skeletal muscle of experimentally galactosemic dogs receiving a placebo or the aldose reductase inhibitor, sorbinil, for 5 yr. The concentration of galactitol was increased more than 30-fold in the retina and other tissues by galactosemia, and the increase was inhibited 90-96% in all tissues by sorbinil. The concentration of free myo-inositol was greater than normal in retinas of galactosemic dogs, and its concentration was not altered by the aldose-reductase inhibitor. The myo-inositol concentration likewise was greater than normal in the retinas of dogs that were diabetic for 2-4 months. The marked inhibition of polyol production and accumulation in the retina of sorbinil-treated galactosemic dogs was not associated with a comparable inhibition of retinopathy.

Topics: Aldehyde Reductase; Alloxan; Animals; Chromatography, Gas; Diabetes Mellitus, Experimental; Disease Models, Animal; Dogs; Erythrocytes; Galactitol; Galactosemias; Imidazoles; Imidazolidines; Inositol; Muscles; Retina

Young beagle dogs were fed a 30% galactose diet, with or without the aldose reductase inhibitors sorbinil or M79175. Cataract formation was monitored by indirect ophthalmoscope and hand-held slit-lamp microscopy and documented by retroillumination photography. In these dogs, the first sign of cataract development was an accentuation of the anterior and posterior lens sutures (1 month after feeding), then the appearance of cortical vacuoles (3 months after feeding), and finally, the formation of predominantly equatorial cortical opacities toward the posterior cortices (4-6 months after feeding). After long-term galactose feeding, a progressive, irregular, clear zone formed at the cortical equatorial regions. Light microscopic examination of these lenses shows that the cataracts are osmotic, many of the lens fibers appear to be swollen or ruptured, and vacuoles are seen near the bow region. Moreover, these histologic changes were reduced in a dose-dependent manner in galactose-fed dogs concomitantly treated with the aldose reductase inhibitors sorbinil or M79175. The osmotic nature of these cataracts and the observation that their formation can be reduced in a dose-dependent manner by aldose reductase inhibitors are consistent with the concept that the aldose-reductase catalyzed formation of polar sugar alcohols (polyols) initiates sugar cataract formation in the dog.

Topics: Aldehyde Reductase; Animals; Cataract; Dietary Carbohydrates; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Galactose; Humans; Imidazoles; Imidazolidines; Lens, Crystalline; Photography; Random Allocation; Rats; Rats, Inbred Strains

The Octodon degus has been reported to have higher aldose reductase activity in the lens compared to the gerbil and rat. When made diabetic the degus develop cataracts within 4 weeks. We have been able to completely prevent cataract formation in diabetic degus using Pfizer's sorbinil for up to 6 months. This is further evidence of the role of aldose reductase in the formation of cataracts in diabetes.

Topics: Aldehyde Reductase; Animals; Cataract; Diabetes Mellitus, Experimental; Disease Models, Animal; Imidazoles; Imidazolidines; Lens, Crystalline; Rodentia; Streptozocin; Sugar Alcohol Dehydrogenases

A twofold thickening of capillary basement membranes of rat retinas resulting from dietary galactose was prevented by sorbinil, an inhibitor of aldose reductase. Since the basement membrane thickening was ultrastructurally similar to that typical of diabetic retinopathy, it may indicate changes in vessel permeability and susceptibility to hemorrhage. Galactosemic rats should be useful models for studying basement membrane-related complications of diabetes and for examining the potential biochemical regulation of basement membrane synthesis by aldose reductase inhibitors.

Topics: Animals; Basement Membrane; Capillaries; Diabetic Retinopathy; Disease Models, Animal; Galactosemias; Imidazoles; Imidazolidines; Male; Rats; Rats, Inbred Strains; Retinal Vessels

Topics: Animals; Cataract; Disease Models, Animal; Galactose; Galactosemias; Glycoproteins; Imidazoles; Imidazolidines; Lens, Crystalline; Proteins; Rats