rhodanine and Hyperglycemia

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

Topics: Aldehyde Reductase; Animals; Calcitriol; Cell Dedifferentiation; Cells, Cultured; Demyelinating Diseases; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Down-Regulation; Enzyme Inhibitors; Glucose; Hyperglycemia; In Vitro Techniques; Insulin-Like Growth Factor I; Mice; Mice, Inbred C57BL; Models, Neurological; Rats; Rhodanine; Schwann Cells; Sciatic Nerve; Sorbitol; Thiazolidines; Vitamin D

To conclude, effective management of hyperglycaemia, symptom control, and prevention of foot ulcers and infection through screening and surveillance remain mainstays of diabetic neuropathy management. Traditional and rational diabetic neuropathy treatments will be supplemented by novel cell based therapy and targeted drug delivery systems in the future.

Topics: Antidepressive Agents, Tricyclic; Diabetic Foot; Diabetic Neuropathies; Enzyme Inhibitors; Humans; Hyperglycemia; Oxidative Stress; Rhodanine; Thiazolidines

We studied the effects of epalrestat, a specific inhibitor of aldose reductase, on renal sorbitol accumulation and the resulting urinary enzyme excretion in hyperglycaemic rats. The activities of proximal tubule-derived enzymes such as N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), gamma-glutamyltranspeptidase (GGT) and dipeptidyl aminopeptidase IV (DAPIV) in urine were determined in five groups of male Wistar rats (each n = 7): (a) 0.9% saline-loaded, (b) 10% glucose-loaded, (c) 10% glucose-loaded with epalrestat pretreatment, (d) 10% mannitol-loaded and (e) 10% mannitol-loaded with epalrestat pretreatment. Epalrestat was given mixed in chow at a dose of 50 mg/kg body weight. Urinary NAG, AAP, GGT and DAPIV activities were significantly increased (P<0.005, P<0.05, P<0.01, P<0.01, respectively) by the induction of hyperglycaemia. In contrast, enzyme excretion was not increased in the mannitol- or saline-loaded groups. Pre-treatment with epalrestat completely prevented the increased urinary excretion of NAG, AAP and GGT. At the end of the infusion study, renal cortical glucose concentrations of the glucose-loaded groups with and without epalrestat pretreatment were approximately fivefold higher than those of the mannitol- or saline-loaded groups (P<0.005 each). Renal cortical sorbitol concentrations of the glucose-loaded group was also approximately twofold higher than those of the mannitol- or saline-loaded groups (P<0.01 each). However, in the group that received both glucose and epalrestat, renal cortical sorbitol concentration was not increased. These results suggest that accumulation of intracellular sorbitol leads to proximal tubular cell dysfunction and abnormal enzymuria.

Topics: Acetylglucosaminidase; Analysis of Variance; Animals; Biomarkers; Blood Glucose; CD13 Antigens; Dipeptidyl Peptidase 4; Enzyme Inhibitors; gamma-Glutamyltransferase; Glomerular Filtration Rate; Glucose; Hyperglycemia; Infusions, Intravenous; Kidney; Male; Mannitol; Rats; Rats, Wistar; Rhodanine; Sorbitol; Thiazolidines; Time Factors

This study was conducted to evaluate effects of the aldose reductase inhibitor ONO-2235 on the contractile response to acetylcholine of the urinary bladder dome of streptozotocin-induced diabetes mellitus (DM) rats and simultaneously observe the changes in the function and number of muscarinic receptors and the sorbitol content of the bladder. The contractile response to acetylcholine increased 51% in the DM rat bladder dome compared to the normal rats; however, this was attenuated to a 10% increase by administration of 100 mg/kg ONO-2235 for 2 weeks. Treatment with ONO-2235 significantly decreased the specific [3H]quinuclidinyl benzilate binding in DM rats. However there was no significant dose-dependency among the ONO-2235-treated groups. The sorbitol levels of the sciatic nerve and the bladder were higher in the DM rats compared to the control rats; ONO-2235 decreased the level, although it did not completely reverse them to the control level. These results suggest that an aldose reductase inhibitor attenuates the increase of the muscarinic receptor number and normalizes the enhanced contractile response to acetylcholine caused by hyperglycemia and diuresis, probably through suppression of the polyol-pathway in the DM rat bladder dome.

Topics: Acetylcholine; Aldehyde Reductase; Analysis of Variance; Animals; Binding, Competitive; Blood Glucose; Diabetes Mellitus, Experimental; Diuresis; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hyperglycemia; Male; Muscle Contraction; Muscle, Smooth; Rats; Rats, Wistar; Receptors, Muscarinic; Rhodanine; Sciatic Nerve; Sorbitol; Thiazolidines; Tissue Preservation; Urinary Bladder

The mechanism by which hyperglycaemia leads to diabetic complications has not been fully elucidated. Non-enzymatic glycosylation leads to considerable functional and structural alteration of proteins. Hyperglycaemia also induces changes in intracellular metabolites, particularly in the polyol pathway. Aldose reductase inhibitors, which block the polyol pathway, have been shown to prevent complications in animal models, and this provides the rationale for the large scale trials that are presently being conducted.

Topics: Aldehyde Reductase; Diabetes Complications; Diabetes Mellitus; Glycolysis; Glycosylation; Humans; Hyperglycemia; Imidazoles; Imidazolidines; Naphthalenes; Phthalazines; Rhodanine; Thiazolidines