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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

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Abstract

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.

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Abbreviations

AKR1B1:

: Human aldose reductase encoded by AKR1B1 gene

AGE:

: Advanced glycation endproducts

BHT:

: Butylated hydroxytoluene

CEM:

: Centre of Experimental Medicine

HbA1c:

: Glycated hemoglobin

MDA:

: Malondialdehyde

RAGE:

: Receptor for AGE

SAS:

: Slovak Academy of Sciences

TBA:

: Thiobarbituric acid

TBARS:

: Thiobarbituric acid reactive substances

TCA:

: Trichloroacetic acid

ZDF:

: Zucker diabetic fatty

References

  1. Singh R, Kishore L, Kaur N (2014) Diabetic peripheral neuropathy: current perspective and future. Directions Pharmacol Res 80:21–35. https://doi.org/10.1016/j.phrs.2013.12.005

    Article  CAS  PubMed  Google Scholar 

  2. Juster-Switlyk K, Smith AG (2016) Updates in diabetic peripheral neuropathy. F1000Res 5 (F1000 Faculty Rev). https://doi.org/10.12688/f1000research.7898.1

    Article  Google Scholar 

  3. Boulton AJ, Kempler P, Ametov A, Ziegler D (2013) Whither pathogenetic treatments for diabetic polyneuropathy? Diabetes Metab Res Rev 29(5):327–333. https://doi.org/10.1002/dmrr.2397

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.7326/M14-0511

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1212/WNL.0000000000003882

    Article  CAS  PubMed  Google Scholar 

  6. Tomlinson DR, Gardiner NJ (2008) Diabetic neuropathies: components of etiology. J Peripher Nerv Syst 13(2):112–121. https://doi.org/10.1111/j.1529-8027.2008.00167.x

    Article  CAS  PubMed  Google Scholar 

  7. Obrosova IG (2009) Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 6(4):638–647. https://doi.org/10.1016/j.nurt.2009.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vincent AM, Callaghan BC, Smith AL, Feldman EL (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7(10):573–583. https://doi.org/10.1038/nrneurol.2011.137

    Article  CAS  PubMed  Google Scholar 

  9. Feldman EL, Nave KA, Jensen TS, Bennett DLH (2017) New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 93(6):1296–1313. https://doi.org/10.1016/j.neuron.2017.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9(1):36–45

    Article  CAS  Google Scholar 

  11. Oates PJ (2008) Aldose reductase, still a compelling target for diabetic neuropathy. Curr Drug Targets 9(1):14–36

    Article  CAS  PubMed  Google Scholar 

  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 16:734–752

    Article  CAS  PubMed  Google Scholar 

  13. Ramana K (2011) Aldose reductase: new insights for an old enzyme. Biomol Concepts 2:103–114. https://doi.org/10.1515/BMC.2011.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1021/jm500907a

    Article  CAS  PubMed  Google Scholar 

  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):120–162

    Article  CAS  PubMed  Google Scholar 

  16. Chalk C, Benstead TJ, Moore F (2007) Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev 4:CD004572. https://doi.org/10.1002/14651858.CD004572.pub2

    Article  Google Scholar 

  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. https://doi.org/10.1016/j.jdiacomp.2009.07.005

    Article  PubMed  Google Scholar 

  18. Ramirez MA, Borja NL (2008) Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28(5):646–655. https://doi.org/10.1592/phco.28.5.646

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1021/jm5015814

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1080/07391102.2018.1465851

    Article  PubMed  Google Scholar 

  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 2321–9009

    Google Scholar 

  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. https://doi.org/10.1179/1351000215Y.0000000019

    Article  CAS  PubMed  Google Scholar 

  23. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol. 52:302–10

    Article  CAS  Google Scholar 

  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):2283–2286

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2337/db11-1524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.pbb.2012.05.008

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.4236/jdm.2014.41011

    Article  CAS  Google Scholar 

  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. https://doi.org/10.2337/db07-1737

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jpain.2015.11.006

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.brainresbull.2016.06.013

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/ejp.1235

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00125-004-1354-2

    Article  CAS  PubMed  Google Scholar 

  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 288508

  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):587–591

    CAS  PubMed  Google Scholar 

  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):1395–1399

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1463-1326.2008.00924.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1155/2010/592760

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.orcp.2014.10.001

    Article  PubMed  Google Scholar 

  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 191:330–338

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Correspondence to Milan Stefek.

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Soltesova Prnova, M., Svik, K., Bezek, S. et al. 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. Neurochem Res 44, 1056–1064 (2019). https://doi.org/10.1007/s11064-019-02736-1

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