Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway

Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks. At 12 weeks after streptozotocin injection, rats were intragastrically administered epalrestat 100 mg/kg daily for 6 weeks. Transmission electron microscope revealed that the injuries to myelinated nerve fibers, non-myelinated nerve fibers and Schwann cells of rat sciatic nerves had reduced compared to rats without epalrestat administuation. Western blot assay and immunohistochemical results demonstrated that after intervention with epalrestat, the activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase gradually increased, but aldose reductase protein expression gradually diminished. Results confirmed that epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway.

Repression of Polyol Pathway Activity by Hemidesmus indicus var.pubescens R.Br.Linn Root Extract,an Aldose Reductase Inhibitor:An In Silico and Ex Vivo Study

Development of diabetic cataract is mainly associated with the accumulation of sorbitol via the polyol pathway through the action of Aldose reductase(AR).Hence,AR inhibitors are considered as potential agents in the management of diabetic cataract.This study explored the AR inhibition potential of Hemidesmus indicus var.pubescens root extract by in silico and ex vivo methods.Molecular docking studies(Auto Dock tool)betweenβ-sitosterol,hemidesminine,hemidesmin-1,hemidesmin-2,and AR showed thatβ-sitosterol(−10.2 kcal/mol)and hemidesmin-2(−8.07 kcal/mol)had the strongest affinity to AR enzyme.Ex vivo studies were performed by incubating isolated goat lenses in artificial aqueous humor using galactose(55 mM)as cataract inducing agent at room temperature(pH 7.8)for 72 h.After treatment with Vitamin E acetate−100μg/mL(standard)and test extract(500 and 1000μg/mL)separately,the estimation of biochemical markers showed inhibition of lens AR activity and decreased sorbitol levels.Additionally,extract also normalized the levels of antioxidant markers like SOD,CAT,GSH.Our results showed evidence that H.indicus var.pubescens root was able to prevent cataract by prevention of opacification and formation of polyols that underlines its potential as a possible therapeutic agent against diabetic complications.

Effect of Pyruvate on Polyol Pathway and Lens Epithelial Cells Apoptosis in Diabetic Rats

Purpose: To investigate the effect of polyol pathway on lens epithelial cells apoptosis and the activity of caspase-3 and its reversal by pyruvate in diabetic rats. Methods: 220 Wister rats were divided into 3 groups: control group, model group and treatment group. After streptozotocin (STZ) induced cataract, the treatment group received 2% pyruvate in the diet and drinking. The opacification of lens was detected by microscope every 2 weeks. On 4W, 8W and 12W of the experiment, glucose and sorbitol in the lens were quantified by high-performance liquid chromatography. The percentage of lens epithelial cells undergoing apoptosis was measured by Annexin Ⅴ/PI staining. The activity of caspase-3 was analyzed by Western-blot. Results: Studies show that there was significant increase of glucose, sorbitol in lens of model group, the apoptosis rate and caspase-3 activity of lens epithelial cells were also gradually increase. Pyruvate treatment decreased the levels of sotbitol, glucose, lens epithelial cells apoptosis and caspase-3 activity. The progress of cataract was also significantly delayed. Conclusions: Polyol pathway, possibly through regulation of the activity of caspase-3, can induce apoptosis of lens epithelial cell. Pyruvate ingested orally can effective inhibit diabetic cataractogenesis in rats through inhibit polyol pathway.

Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase

Background Berberine is one of the main constituents of Coptidis rhizoma （CR） and Cortex phellodendri. In this study, we investigated the beneficial effects of berberine on renal function and its possible mechanisms in rats with diabetic nephropathy （DN）. Methods Male Wistar rats were divided into three groups： normal, diabetic model, and berberine treatment groups. Rats in the diabetic model and berberine treatment groups were induced to diabetes by intraperitonal injection with streptozotocin （STZ）. Glomerular area, glomerular volume, fasting blood glucose （FBG）, blood urea nitrogen （BUN）, serum creatinine （Cr） and urine protein for 24 hours （UP24h） were measured using commercially available kits. Meanwhile, the activity of superoxide dismutase （SOD）, content of malondialdehyde （MDA） in serum, activity of aldose reductase （AR） and the expression of AR mRNA and protein in kidney were detected by different methods. Results The results showed that oral administration of berberine （200 mg·kg^-1·d^-1） significantly ameliorated the ratio of kidney weight to body weight. Glomerular area, glomerular volume, FBG, BUN, Cr and UP24h were significantly decreased in the berberine treatment group compared with the diabetic model group （P〈0.05）. Berberine treatment significantly increased serum SOD activity and decreased the content of MDA compared with diabetic model group （P 〈0.05）. AR activity as well as the expression of AR mRNA and protein in the kidney was markedly decreased in the berberine treatment group compared with diabetic model group （P 〈0.05）. Conclusion These results suggested that berberine could ameliorate renal dysfunction in DN rats through controlling blood glucose, reduction of oxidative stress and inhibition of the activation of the polyol pathway.

Pharmacologically tested aldose reductase inhibitors isolated from plant sources—A concise report

Aldose reductase (AR), a cytosolic, monomeric oxidoreductase, is a key enzyme in the polyol pathway which controls the conversion of glucose to sorbitol. The accumulation of sorbitol by the activation of AR enzymes in lens, retina, and sciatic nerves leads to the cause of diabetic defects resulting in various secondary complications, viz. retinopathy, neuropathy, nephropathy and Alzheimer's disease. Thus, reduction of the polyol pathway flux by AR inhibitors could be a potential therapeutic opening in the treatment and prevention of diabetic complications. At present, the AR inhibitors belong to two different chemical classes. One is the hydantoin derivatives, such as Sorbinil, Dilantin, and Minalrestat, and the other is the carboxylic acid derivatives, such as Epalrestat, Alrestatin, and Tolrestat. However, it is known that most of these synthethic compounds have unacceptable side-effects. Well known medicinal plants like Chrysanthemum indicum, Chrysanthemum morifolium, Prunus mume, Myrcia multiflora, Centella asiatica, and Salacia reticulata, Salacia oblonga, and Salacia chinensis exhibited potent AR inhibitory activity. The present review summarizes the list of plant material, and their isolated phytoconstituents which have been tested for their AR inhibitory activity. This litreature review covers the period to 2011, and a total of 72 plants are listed.