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

  • Marta Soltesova Prnova
  • Karol Svik
  • Stefan Bezek
  • Lucia Kovacikova
  • Cimen Karasu
  • Milan StefekEmail author
Original Paper


Peripheral neuropathy is the most prevalent chronic complication of diabetes mellitus. Good glycemic control can delay the appearance of neuropathic symptoms in diabetic patients but it is not sufficient to prevent or cure the disease. Therefore therapeutic approaches should focus on attenuation of pathogenetic mechanisms responsible for the nerve injury. Considering the role of polyol pathway in the etiology of diabetic neuropathy, we evaluated the effect of a novel efficient and selective aldose reductase inhibitor, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (cemtirestat), on symptoms of diabetic peripheral neuropathy in Zucker Diabetic Fatty (ZDF) rats. Since the age of 5 months, male ZDF rats were orally administered cemtirestat, 2.5 and 7.5 mg/kg/day, for two following months. Thermal hypoalgesia was evaluated by tail flick and hot plate tests. Tactile allodynia was determined by a von Frey flexible filament test. Two-month treatment of ZDF rats with cemtirestat (i) did not affect physical and glycemic status of the animals; (ii) partially inhibited sorbitol accumulation in red blood cells and the sciatic nerve; (iii) markedly decreased plasma levels of thiobarbituric acid reactive substances; (iv) normalized symptoms of peripheral neuropathy with high significance. The presented findings indicate that inhibition of aldose reductase by cemtirestat is not solely responsible for the recorded improvement of the behavioral responses. In future studies, potential effects of cemtirestat on consequences of diabetes that are not exclusively dependent on glucose metabolism via polyol pathway should be taken into consideration.


Aldose reductase inhibitor Cemtirestat Diabetic peripheral neuropathy Zucker diabetic fatty rats Oxidative stress 



: Human aldose reductase encoded by AKR1B1 gene


: Advanced glycation endproducts


: Butylated hydroxytoluene


: Centre of Experimental Medicine


: Glycated hemoglobin


: Malondialdehyde


: Receptor for AGE


: Slovak Academy of Sciences


: Thiobarbituric acid


: Thiobarbituric acid reactive substances


: Trichloroacetic acid


: Zucker diabetic fatty



This work was supported by SAS-Tubitak JRP 2015/7, Slovak Research and Development Agency under the Contract No. APVV-15-0455, VEGA 2/0005/2018, and TUBITAK Project No: 215S19.


  1. 1.
    Singh R, Kishore L, Kaur N (2014) Diabetic peripheral neuropathy: current perspective and future. Directions Pharmacol Res 80:21–35. CrossRefGoogle Scholar
  2. 2.
    Juster-Switlyk K, Smith AG (2016) Updates in diabetic peripheral neuropathy. F1000Res 5 (F1000 Faculty Rev). Google Scholar
  3. 3.
    Boulton AJ, Kempler P, Ametov A, Ziegler D (2013) Whither pathogenetic treatments for diabetic polyneuropathy? Diabetes Metab Res Rev 29(5):327–333. CrossRefGoogle Scholar
  4. 4.
    Griebeler ML, Morey-Vargas OL, Brito JP, Tsapas A, Wang Z, Carranza Leon BG, Phung OJ, Montori VM, Murad MH (2014) Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med 161(9):639–649. CrossRefGoogle Scholar
  5. 5.
    Waldfogel JM, Nesbit SA, Dy SM, Sharma R, Zhang A, Wilson LM, Bennett WL, Yeh HC, Chelladurai Y, Feldman D, Robinson KA (2017) Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 88(20):1958–1967. CrossRefGoogle Scholar
  6. 6.
    Tomlinson DR, Gardiner NJ (2008) Diabetic neuropathies: components of etiology. J Peripher Nerv Syst 13(2):112–121. CrossRefGoogle Scholar
  7. 7.
    Obrosova IG (2009) Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 6(4):638–647. CrossRefGoogle Scholar
  8. 8.
    Vincent AM, Callaghan BC, Smith AL, Feldman EL (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7(10):573–583. CrossRefGoogle Scholar
  9. 9.
    Feldman EL, Nave KA, Jensen TS, Bennett DLH (2017) New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 93(6):1296–1313. CrossRefGoogle Scholar
  10. 10.
    Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9(1):36–45CrossRefGoogle Scholar
  11. 11.
    Oates PJ (2008) Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets 9(1):14–36CrossRefGoogle Scholar
  12. 12.
    Alexiou P, Pegklidou K, Chatzopoulou M, Nicolaou I, Demopoulos VJ (2009) Aldose reductase enzyme and its implication to major health problems of the 21(st) century. Curr Med Chem 16:734–752CrossRefGoogle Scholar
  13. 13.
    Ramana K (2011) Aldose reductase: new insights for an old enzyme. Biomol Concepts 2:103–114. CrossRefGoogle Scholar
  14. 14.
    Maccari R, Ottanà R (2015) Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions. J Med Chem 58:2047–2067. CrossRefGoogle Scholar
  15. 15.
    Grewal AS, Bhardwaj S, Pandita D, Lather V, Sekhon BS (2016) Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Rev Med Chem 16(2):120–162CrossRefGoogle Scholar
  16. 16.
    Chalk C, Benstead TJ, Moore F (2007) Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev 4:CD004572. Google Scholar
  17. 17.
    Schemmel KE, Padiyara RS, D’Souza JJ (2010) Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review. J Diabetes Complications 24(5):354–360. CrossRefGoogle Scholar
  18. 18.
    Ramirez MA, Borja NL (2008) Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28(5):646–655. CrossRefGoogle Scholar
  19. 19.
    Stefek M, Soltesova Prnova M, Majekova M, Rechlin C, Heine A, Klebe G (2015) Identification of novel aldose reductase inhibitors based on carboxymethylated mercaptotriazinoindole scaffold. J Med Chem 58(6):2649–2657. CrossRefGoogle Scholar
  20. 20.
    Zhan JY, Ma K, Zheng QC, Yang GH, Zhang HX (2018) Exploring the interactional details between aldose reductase (AKR1B1) and 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid through molecular dynamics simulations. J Biomol Struct Dyn. Google Scholar
  21. 21.
    Stefek M, Soltesova Prnova M, Ballekova J, Majekova M (2016) Cemtirestat, a novel aldose reductase inhibitor and antioxidant, in multitarget pharmacology of diabetic complications. IRAJ 4(3):41–44. ISSN 2321–9009Google Scholar
  22. 22.
    Prnova MS, Ballekova J, Majekova M, Stefek M (2015) Antioxidant action of 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid, an efficient aldose reductase inhibitor, in a 1,1′-diphenyl-2-picrylhydrazyl assay and in the cellular system of isolated erythrocytes exposed to tert-butyl hydroperoxide. Redox Rep 20(6):282–288. CrossRefGoogle Scholar
  23. 23.
    Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol. 52:302–10CrossRefGoogle Scholar
  24. 24.
    Mylari BL, Armento SJ, Beebe DA, Conn EL, Coutcher JB, Dina MS, O’Gorman MT, Linhares MC, Martin WH, Oates PJ, Tess DA, Withbroe GJ, Zembrowski WJ (2003) A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2-H-pyridazin-3-one. J Med Chem 46(12):2283–2286CrossRefGoogle Scholar
  25. 25.
    Shevalye H, Watcho P, Stavniichuk R, Dyukova E, Lupachyk S, Obrosova IG (2012) Metanx alleviates multiple manifestations of peripheral neuropathy and increases intraepidermal nerve fiber density in Zucker diabetic fatty rats. Diabetes 61(8):2126–2133. CrossRefGoogle Scholar
  26. 26.
    Vera G, López-Miranda V, Herradón E, Martín MI, Abalo R (2012) Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes. Pharmacol Biochem Behav 102(2):335–343. CrossRefGoogle Scholar
  27. 27.
    Lupachyk S, Shevalye H, Watcho P, Obrosov A, Obrosova IG, Yorek MA (2014) Treatment of peripheral diabetic neuropathy in Zucker diabetic fatty (ZDF) rats with cariporide. J Diabetes Mellitus 4:59–66. CrossRefGoogle Scholar
  28. 28.
    Brussee V, Guo G, Dong Y, Cheng C, Martinez JA, Smith D, Glazner GW, Fernyhough P, Zochodne DW (2008) Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model. Diabetes 57(6):1664–1673. CrossRefGoogle Scholar
  29. 29.
    Griggs RB, Donahue RR, Adkins BG, Anderson KL, Thibault O, Taylor BK (2016) Pioglitazone inhibits the development of hyperalgesia and sensitization of spinal nociresponsive neurons in type 2 diabetes. J Pain 17(3):359–373. CrossRefGoogle Scholar
  30. 30.
    Yang Y, Zhang Z, Guan J, Liu J, Ma P, Gu K, Zhao J, Yang G, Song T (2016) Administrations of thalidomide into the rostral ventromedial medulla alleviates painful diabetic neuropathy in Zucker diabetic fatty rats. Brain Res Bull 125:144–151. CrossRefGoogle Scholar
  31. 31.
    Garcia-Perez E, Schönberger T, Sumalla M, Stierstorfer B, Solà R, Doods H, Serra J, Gorodetskaya N (2018) Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats. Eur J Pain. Google Scholar
  32. 32.
    Calcutt NA, Freshwater JD, Mizisin AP (2004) Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor. Diabetologia 47(4):718–724. CrossRefGoogle Scholar
  33. 33.
    Stefek M, Milackova I, Díez-Dacal B, Pérez-Sala D, Soltesova Prnova M (2017) Use of 5-carboxymethyl-3-mercapto-1,2,4-triazino-[5,6-b]indoles and their pharmaceutical composition. Slovak Patent No 288508Google Scholar
  34. 34.
    Soltesova Prnova M, Ballekova J, Gajdosikova A, Gajdosik A, Stefek M (2015) A novel carboxymethylated mercaptotriazinoindole inhibitor of aldose reductase interferes with the polyol pathway in streptozotocin-induced diabetic rats. Physiol Res 64(4):587–591Google Scholar
  35. 35.
    Shimoshige Y, Ikuma K, Yamamoto T, Takakura S, Kawamura I, Seki J, Mutoh S, Goto T (2000) The effects of zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats. Metabolism 49(11):1395–1399CrossRefGoogle Scholar
  36. 36.
    Oltman CL, Davidson EP, Coppey LJ, Kleinschmidt TL, Yorek MA (2009) Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes Metab 11(3):223–233. CrossRefGoogle Scholar
  37. 37.
    Ferreira L, Teixeira-de-Lemos E, Pinto F, Parada B, Mega C, Vala H, Pinto R, Garrido P, Sereno J, Fernandes R, Santos P, Velada I, Melo A, Nunes S, Teixeira F, Reis F (2010) Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators Inflamm 2010:592760:1–11. CrossRefGoogle Scholar
  38. 38.
    Wakabayashi I, Shimomura T, Nakanishi M, Uchida K (2015 Jan-Feb) Elevation of circulating LOX-1 ligand levels in Zucker obese and diabetic rats. Obes Res Clin Pract 9(1):26–30. CrossRefGoogle Scholar
  39. 39.
    Srivastava SK, Yadav UC, Reddy AB, Saxena A, Tammali R, Shoeb M, Ansari NH, Bhatnagar A, Petrash MJ, Srivastava S, Ramana KV (2011) Aldose reductase inhibition suppresses oxidative stress-induced inflammatory disorders. Chem Biol Interaction 191:330–338CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Marta Soltesova Prnova
    • 1
  • Karol Svik
    • 1
  • Stefan Bezek
    • 1
  • Lucia Kovacikova
    • 1
  • Cimen Karasu
    • 2
  • Milan Stefek
    • 1
    Email author
  1. 1.Department of Biochemical Pharmacology, Institute of Experimental Pharmacology and ToxicologyCEM, Slovak Academy of SciencesBratislavaSlovakia
  2. 2.Department of Medical Pharmacology, Faculty of MedicineGazi UniversityBeşevlerTurkey

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