Monotherapy of experimental metabolic syndrome: I. Efficacy and safety

Štefan Bezek 1 , Zuzana Brnoliaková 1 , Ružena Sotníková 1 , Vladimír Knezl 1 , Ema Paulovičová 2 , Jana Navarová 1  and Viktor Bauer 1
  • 1 Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04, Bratislava, Slovakia
  • 2 Institute of Chemistry, Slovak Academy of Sciences, 841 04, Bratislava, Slovakia


Elevated plasma cholesterol, especially low density lipoprotein (LDL) cholesterol, is one of the major risk factors for atherosclerosis and coronary heart disease. Hereditary hypertriglyceridemic rats (hHTG) were developed as a new inbred model for the study of relationships between blood pressure and metabolic abnormalities. The aim of this work was to determine the cholesterol-lowering and antioxidant effects of the novel pyridoindol derivative SMe1EC2, compared to the cholesterol-lowering drug atorvastatin, in rats fed either standard or high-fat and high-cholesterol diet (HFC; 1% cholesterol and 7.5% lard fat). Male hHTG rats fed HFC (HTG+HFC) were administered with SMe1EC2 or atorvastatin (both 50 mg/kg/day p.o.) for 4 weeks. Physiological status of animals was monitored by the measurement of preprandial glucose levels and blood pressure. Lipid profile was characterized by the serum levels of total cholesterol (TC), HDL-, LDL-cholesterol and triglycerides (TRG). The concentration of thiobarbituric acid reactive substances (TBARS) was evaluated in the kidney, liver and serum. Further, the assessment of pro-inflammatory cytokines TNF-α, IL-1 and IL-6 in the serum was completed. Feeding the animals with HFC diet resulted in increased serum levels of TC, LDL and TRG. SMe1EC2 ameliorated serum levels of LDL in hHTG rats, both on standard and HFC diet. These effects were comparable with those of the standard hypolipidemicum atorvastatin. SMe1EC2 lowered blood pressure, tissue TBARS concentrations and serum IL-1 levels of HTG+HFC rats. Beneficial effects together with very good toxicity profile predestinate SMe1EC2 to be promising agent for further surveys related to metabolic syndrome features.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • American Diabetes Association (2002). Management of dyslipidemia in adults with diabetes. Diabetes Care 25: 74–77.

  • Balcerczyk A, Bartosz G, Drzewinska J, Piotrowski Ł, Pulaski Ł, Stefek M. (2014). Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level. Interdiscip Toxicol 7: 27–32.

  • Davidson M. (2008). Review of the current status of the management of mixed dyslipidemia associated with diabetes mellitus and metabolic syndrome. Am J Cardiol 102:19L–27L.

  • De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. (2003). European guidelines on cardiovascular disease prevention in clinical practice: Third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 10: S1–10.

  • Drimal J, Knezl V, Navarova J, Nedelcevova J, Paulovicova E, Sotnikova R, Snirc V, Drimal D. (2008). Role of inflammatory cytokines and chemoattractants in the rat model of streptozotocin-induced diabetic heart failure. Endocr Regul 42: 129–135.

  • Gáspárová Z, Snirc V, Stolc S. (2011). The new pyridoindole antioxidant SMe1EC2 and its intervention in hypoxia/hypoglycemia-induced impairment of longterm potentiation in rat hippocampus. Interdiscip Toxicol 4: 56–61.

  • Isomaa B. (2003). A major health hazard: the metabolic syndrome. Life Sci 73: 2395–2411.

  • Kabaklić A, Fras Z. (2017). Moderate-dose atorvastatin improves arterial endothelial function in patients with angina pectoris and normal coronary angiogram: a pilot study. Arch Med Sci 13: 827–836.

  • Klimes I, Vrána A, Kunes J, Seböková E, Dobesová Z, Stolba P, Zicha J. (1995). Hereditary hypertriglyceridemic rat: a new animal model of metabolic alterations in hypertension. Blood Press 4: 137–142.

  • Knezl V, Sotníková R, Brnoliaková Z, Bauer V, Bezek Š. (2017). Monotherapy of experimental metabolic syndrome II. Study of cardiovascular effects. Interdiscip Toxicol 10(2):

  • Kwasny C, Manuwald U, Kugler J, Horm U. (2017). Systematic review of the epidemiology and natural history of the metabolic vascular syndrome and its coincidence with Type 2 diabetes mellitus and cardiovascular diseases in different european countries. Metab Res. doi: 10.1055/s-0043-122395. [Epub ahead of print]PMID:29183091) ].

  • Liao JK. (2002). Beyond lipid lowering: The role of statins in vascular protection. Int J Cardiol 86: 5–18.

  • Mendrick DL, Diehl AM, Topor LS, Dietert RR, Will Y, La Merrill MA, Bouret S, Varma V, Hastings KL, Schug TT, Emeigh Hart SG, Burleson FG. (2017). Metabolic syndrome and associated diseases: From the bench to the clinic. Toxicol Sci doi: 10.1093/toxsci/kfx233. [Epub ahead of print].

  • Meerarani P, Badimon JJ, Zias E, Fuster V, Moreno PR. (2006). Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications. Curr Mol Med 6: 501–514.

  • Mézešová L, Jendruchová-Javorková V, Vlkovičová J, Kyselova Z, Navarová J, Bezek S, Vrbjar N. (2012). Antioxidant SMe1EC2 may attenuate the disbalance of sodium homeostasis in the organism induced by higher intake of cholesterol. Mol Cell Biochem 366: 41–48.

  • Paravicini TM and Touyz RM. (2006). Redox signaling in hypertension. Cardiovasc Res 71: 247–258.

  • Pekiner B, Ulusu, NN, Das-Evcimen N, Sahilli M, Aktan F, Stefek M, Stolc S, Karasu I. (2002). In vivo treatment with stobadine prevents lipid peroxidation, protein glycation and calcium overload but does not ameliorate Ca2+-ATPase activity in heart and liver of streptozotocin-diabetic rats: comparison with vitamin E. Biochim Biophys Acta 1588: 71–78.

  • Raal FJ. (2009). Pathogenesis and management of the dyslipidemia of the metabolic syndrome. Metab Syndr Relat Disord 7: 83–88.

  • Rai KN, Kumari NS, Gowda Km D, Kr S (2013). The evaluation of micronutrients and oxidative stress and their relationship with the lipid profile in healthy adults. J Clin Diagn Res. 7: 1314–1318.

  • Stefek M, Sotnikova R, Okruhlicova L, Volkovova K, Kucharska J. (2000). Effect of dietary supplementation with the pyridoindole antioxidant stobadine on antioxidant state and ultrastructure of diabetic rat myocardium. Acta Diabetol 37: 111–117.

  • Štolc S, Šnirc V, Májeková M, Gáspárová Z, A. Gajdošíková A, Štvrtina S. (2006). Development of the new group of indole-derived neuroprotective drugs affecting oxidative stress. Cell Mol Neurobiol 26: 1493–1502.

  • Ujhazy E, Dubovicky M, Ponechalova V, Navarova J, Brucknerova I, Snirc V, Mach M. (2008). Prenatal developmental toxicity study of the pyridoindole antioxidant SMe1EC2 in rats. Neuro Endocrinol Lett 29: 639–643.

  • Ujhazy E, Mach M, Navarova J, Brucknerova I, Dubovicky M. (2011). Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats. Interdiscip Toxicol 4: 47–51.

  • Vakhrushev YM, Lyapina MV (2017). Enteral failure and metabolic syndrome: Common neurohormonal mechanisms of development, possibilities of their rational therapy. Ter Arkh. 89: 95–101.

  • Wihastuti TA and Heriansyah T. (2017). The inhibitory effects of polysaccharide peptides (PsP) of Ganoderma lucidum against atherosclerosis in rats with dyslipidemia. Heart Int 12: e1–e7.

  • Yamada Y, Takeuchi S, Yoneda M, Ito S, Sano Y, Nagasawa K, Matsuura N, Uchinaka A, Murohara T, Nagata K. (2017). Atorvastatin reduces cardiac and adipose tissue inflammation in rats with metabolic syndrome. Int J Cardiol 240: 332–338.

  • Zamani E, Mohammadbagheri M, Fallah M, Shaki F. (2017). Atorvastatin attenuates ethanol-induced hepatotoxicity via antioxidant and anti-inflammatory mechanisms. Res Pharm Sci 12: 315–321.

  • Zicha J, Pechanova O, Cacanyiova S, Cebova M, Kristek F, Torok J, Simko F, Dobesova Z, Kunes J. (2006). Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome? Physiol Res 55: S49–S63.


Journal + Issues