epalrestat and Disease-Models--Animal

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

Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation and affects over 1000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. To identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multispecies drug repurposing screen using a novel worm model of PMM2-CDG, followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts. Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the worm-based phenotypic screen, 12 were plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a first-in-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.

Topics: Aldehyde Reductase; Animals; Cells, Cultured; Congenital Disorders of Glycosylation; Diabetic Neuropathies; Disease Models, Animal; Drug Repositioning; Endoplasmic Reticulum Stress; Fibroblasts; Glycosylation; Humans; Nematoda; Phosphotransferases (Phosphomutases); Polyphenols; Rhodanine; Thiazolidines

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

Antioxidant defense is an essential mechanism for schistosomes to cope with damage from host immune-generated reactive oxygen species. The evaluation of the effects of aldose reductase, an important enzyme that may be involved in this system, has long been neglected. In the present study, aldose reductase of Schistosoma japonicum (SjAR) was cloned and characterized. The activity of SjAR was assessed in vitro and was suppressed by the reported inhibitor, epalrestat. RT-PCR analysis revealed that SjAR was expressed at each of the development stages analyzed with increased levels in cercariae. The results also showed that SjAR was expressed at higher levels in adult male worms than in adult female worms. Indirect enzyme-linked immunosorbent assay and western blot analysis indicated that the purified recombinant SjAR (rSjAR) protein displayed a significant level of antigenicity. Immunolocalization analysis revealed that SjAR was mainly distributed in the gynecophoral canal of adult male worms. BALB/c mice immunized with rSjAR induced a 32.91 % worm reduction compared to the adjuvant group (P < 0.01). Moreover, a 28.27 % reduction in egg development in the liver (P > 0.05) and a 42.75 % reduction in egg development in the fecal samples (P < 0.05) were also observed. These results suggested that SjAR may be a potential new drug target or vaccine candidate for schistosomes.

Topics: Aldehyde Reductase; Amino Acid Sequence; Animals; Antigens, Helminth; Blotting, Western; Cloning, Molecular; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Male; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; Rhodanine; Schistosoma japonicum; Schistosomiasis japonica; Thiazolidines; Vaccination; Vaccines, Synthetic

Many observations report the cardioprotective effects of inhibitors of aldose reductase in different models of ischaemia-reperfusion injury in diabetic myocardium. In this paper, the inhibitory effects of the new pyrido[1,2-a]-pyrimidin-4-one derivative PPO, whose aldose reductase-inhibitory and antioxidant effects were shown in a previous study, were evaluated.. The effect of PPO was evaluated on aldose reductase from hearts of diabetic and non-diabetic rats, and compared with that of the reference drug epalrestat. Moreover, the two drugs were tested on isolated and Langendorff-perfused diabetic and non-diabetic hearts submitted to ischaemia-reperfusion cycle.. Epalrestat showed equivalent levels of potency in inhibiting the activity of the enzyme in the diabetic and in the non-diabetic hearts. On the contrary, the inhibitory potency of PPO was decreased in the diabetic organs. In the diabetic hearts submitted to ischaemia-reperfusion, an increased level of heart aldose reductase activity was recorded, and both PPO and epalrestat produced cardioprotective effects, suggesting that aldose reductase is deeply involved in the process of ischaemia-reperfusion injury in diabetic myocardium. In non-diabetic hearts, where aldose reductase has a lower activity, epalrestat failed to produce significant protection, while PPO still maintained cardioprotective effects, which may be reasonably attributed to useful 'ancillary' effects - such as antioxidant activity - independent from the aldose reductase inhibition.. Therefore PPO, a new molecule endowed with both aldose reductase-inhibitory effects and antioxidant activity, may represent the prototype of a new class of multitarget drugs, focused on two different steps deeply involved in the pathogenesis of ischaemic injury of diabetic hearts.

Topics: Aldehyde Reductase; Animals; Antioxidants; Cardiotonic Agents; Diabetes Mellitus, Experimental; Disease Models, Animal; Enzyme Inhibitors; Male; Myocardial Reperfusion Injury; Myocardium; Pyridines; Pyrimidinones; Rats; Rats, Wistar; Rhodanine; Thiazolidines