3-Mercapto-5H-1,2,4-Triazino[5,6-b]Indole-5-Acetic Acid (Cemtirestat) Alleviates Symptoms of Peripheral Diabetic Neuropathy in Zucker Diabetic Fatty (ZDF) Rats: A Role of Aldose Reductase

Prnová, Marta Šoltésová; Švík, Karol; Bezek, S; Kovacikova, Lucia; Karasu, Çi̇men; Štefek, Milan

doi:10.1007/s11064-019-02736-1

Cited by 18 publications

(19 citation statements)

References 37 publications

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“…Aldose reductase thus represents a promising therapeutic target and efficient aldose reductase inhibitors are sought as potential drugs to treat diabetic complications. In our recent study in ZDF rats, an animal model of type 2 diabetes, cemtirestat normalized symptoms of peripheral neuropathy with high significance (Soltesova Prnova et al 2019). Inhibition of sorbitol accumulation in red blood cells and in the sciatic nerve along with markedly decreased plasma levels of thiobarbituric acid reactive substances pointed to the bifunctional effect of cemtirestat comprising both inhibition of flux of glucose through the polyol pathway and antioxidant action.…”

Section: Introductionmentioning

confidence: 91%

“…Piešťany, Slovakia. Plasma levels of thiobarbituric acid reactive substances (TBARS), used as a marker of oxidative stress, were determined by modification of the method of Buege and Aust (Buege and Aust, 1978) as described previously (Soltesova Prnova et al, 2019).…”

Section: Plasma Assaysmentioning

confidence: 99%

“…Erythrocyte sorbitol assay was performed by modified enzymatic assay as reported previously (Soltesova Prnova et al, 2019).…”

Section: Sorbitol Assaymentioning

confidence: 99%

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General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Prnová

Račková

Kovacikova

et al. 2019

Interdisciplinary Toxicology

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Cemtirestat, 3-mercapto-5H-[1,2,4]-triazino[5,6-b]indole-5-acetic acid was recently designed and patented as a highly selective and efficient aldose reductase inhibitor endowed with antioxidant activity. The aim of the present study was to assess the general toxicity of cemtirestat using in silico predictions, in vitro and in vivo assays. ProTox-II toxicity prediction software gave 17 “Inactive” outputs, a mild hepatotoxicity score (0.52 probability) along with a predicted LD50 of 1000 mg/kg. Five different cell lines were used including the immortalized mouse microglia BV-2, the primary human fibroblasts VH10, the insulinoma pancreatic β-cells INS-1E, the human colon cancer cells HCT116 and the human immortalized epithelial endometrial cell lines HIEEC. In contrast to the clinically used epalrestat, cemtirestat showed remarkably low cytotoxicity in several different cell culture viability tests such as MTT proliferation assay, neutral red uptake, BrdU incorporation, WST-1 proliferation assay and propidium iodide staining followed by flow cytometry. In a yeast spotting assay, the presence of cemtirestat in incubation of Saccaromyces cerevisiae at concentrations as high as 1000 µM did not affect cell growth rate significantly. In the 120-day repeated oral toxicity study in male Wistar rats with daily cemtirestat dose of 6.4 mg/kg, no significant behavioral alterations or toxicological manifestations were observed in clinical and pathological examinations or in hematological parameters. In summary, these results suggest that cemtirestat is a safe drug that can proceed beyond preclinical studies.

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Section: Introductionmentioning

confidence: 91%

Section: Plasma Assaysmentioning

confidence: 99%

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General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Prnová

Račková

Kovacikova

et al. 2019

Interdisciplinary Toxicology

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“…At the age of 5 months, fatty ZDF rats developed significant symptoms of thermal hypoalgesia indicated by prolonged response latencies in a tail-flick test. With progressing diabetes, the markers of thermal hypoalgesia increased at the age of 7 months and persisted till the 10th month [10]. The ZDF rats undergo a rapid transition between 10 and 15 weeks of age.…”

Section: Zucker Diabetic Fatty Ratsmentioning

confidence: 97%

“…The determining points involve multiple mechanisms of glucose toxicity including polyol pathway activity, hexosamine pathway, nonenzymatic glycations of proteins, and altered protein kinase C activity [9]. Activation of these pathways can eventually flow into inflammatory and oxidative stress in neurons and adjacent microvascular system [10].…”

Section: Diabetes Mellitusmentioning

confidence: 99%

Zucker Diabetic Fatty Rats for Research in Diabetes

Capcarová¹,

Kalafová²

2020

Animal Models in Medicine and Biology

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The rising incidence of diabetes mellitus (DM) worldwide presents a global public health problem. DM is classified into two main groups: type 1 (T1DM) and type 2 (T2DM). T1DM requires insulin treatment. T2DM is complex, heterogeneous, polygenic disease defined primarily by insulin resistance, ongoing hyperglycemia, and β cells' dysfunction. For research in diabetes, an appropriate experimental model reflecting symptoms and complications of human T2DM is required for understanding the pathogenesis, molecular nature, and the possibilities of the treatment. Among the many animal models, rodent models that develop DM spontaneously are frequently used in the studies due to their similarity to the humans and economic effectiveness. This work gives a detailed overview of the literature, covering the characteristic of DM, its symptoms and complications, the description of Zucker diabetic fatty (ZDF) rats as an appropriate model for research in T2DM, and the possibility of the treatment.spontaneously diabetic Tori (SDT) rats, Kuo Kondo (KK) mice, ob/ob+/+ mice, and db/db+/+ mice [84]. GK rats are nonobese Wistar substrain which develops T2DM early [86]. Male OLETS rats suffer from diabetes at 18-25 weeks of age. The symptoms include polyphagia, mild obesity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance in 16 weeks of age [87]. Tori SDT rat is inbred strain of Sprague-Dawley rat. Male individuals have high glucose levels by 20 weeks, pancreatic islet histopathology, hemorrhage in pancreatic islets, and inflammatory cell infiltration with fibroblasts, prior to diabetes glucose intolerance with hypoinsulinemia [88].KK mice are a polygenic model of obesity and T2DM. They are characterized by insulin resistance, hyperinsulinemia, and hyperphagia [89]. The ob/ob+/+ mice carry a mutation in the leptin gene, manifested as obesity, hyperglycemia, impaired glucose intolerance, and hyperinsulinemia [90]. The db/db+/+ mice have a leptin receptor mutation, are spontaneously hyperphagic, and suffer from obesity, hyperglycemia, hyperinsulinemia, and insulin resistance within the first month of life [91]. The advantages of ZDF rats in diabetes research are mainly due to the fact that it is a spontaneous model for T2DM research. It shows characteristics such as hyperglycemia, obesity, hyperphagia, polyuria, insulin disorders, and dyslipidemia due to the mutation in the leptin receptor gene and provides an appropriate model for common human T2DM. Moreover, these rats are calm and dispassionate; the handling and manipulation with them is comfortable.

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Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity

Reihanifar,

Şahin,

Stefek

et al. 2023

Cell Biochemistry & Function

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Fructose, endogenously produced as a consequence of activation of the polyol pathway under hyperglycemic conditions, contribute to formation of advanced glycoxidation end products (AGEs) and carbonyl stress. Oxidative stress is increased in diabetes (DM) due to AGEs formation and the utilization of NADPH by aldo‐keto reductase, AKR1B1(AR), the first enzyme in polyol pathway. Since inhibition of AR is an attractive approach for the management of diabetic eye diseases, we aimed to compare the effects of a novel AR inhibitor (ARI)/antioxidant (AO) compound cemtirestat on eye tissues with the effects of ARI drug epalrestat and AO agent stobadine in rat model for glycotoxicity. One group of rats was fed high fructose (10% drinking water; 14 weeks), while type‐2 DM was induced in the other group of rats with fructose plus streptozotocin (40 mg/kg‐bw/day). Diabetic (D) and nondiabetic fructose‐fed rats (F) were either untreated or treated with two different doses of cemtirestat (2.5 and 7.5 mg/kg‐bw/day), epalrestat (25 and 50 mg/kg‐bw/day), or stobadine (25 and 50 mg/kg‐bw/day) for 14 weeks. Cemtirestat, epalrestat, and stobadine elaviate the increase in TNF‐α, IL‐1β, NF‐ƙB, and caspase‐3 in retina, lens, cornea, and sclera of F and D rats. Both glycotoxicity models resulted in a decrease in GSH to GSSG ratio and a change in glutathione S‐transferase activity in eye tissues, but these alterations were improved especially with cemtirestat and stobadine. Lens D‐sorbitol of D rats increased more than that of F rats, this increase was only attenuated by cemtirestat and epalrestat. Epalrestat was more effective than cemtirestat and stobadine in inhibiting the increase of vascular endothelial growth factor (VEGF) in the retina of F and D rats. Cemtirestat and stobadine but not epalrestat decreased high level of Nε‐(carboxymethyl)lysine in the lens and retina of F and D rats. Cemtirestat is a potential therapeutic in protecting the rat eye against glycotoxicity insults.

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3-Mercapto-5H-1,2,4-Triazino[5,6-b]Indole-5-Acetic Acid (Cemtirestat) Alleviates Symptoms of Peripheral Diabetic Neuropathy in Zucker Diabetic Fatty (ZDF) Rats: A Role of Aldose Reductase

Cited by 18 publications

References 37 publications

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

General toxicity assessment of the novel aldose reductase inhibitor cemtirestat

Zucker Diabetic Fatty Rats for Research in Diabetes

Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity

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