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Endocrine, Metabolic & Immune Disorders - Drug Targets

Author(s): Svetlana Yagubova, Aliy Zhanataev, Rita Ostrovskaya*, Еlena Anisina, Тatiana Gudasheva, Аndrey Durnev and Sergey Seredenin

DOI: 10.2174/1871530319666190806115623

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Dimeric NGF Mimetic Attenuates Hyperglycaemia and DNA Damage in Mice with Streptozotocin-Induced Early-Stage Diabetes

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Abstract

Background: NGF deficiency is one of the reasons for reduced β-cells survival in diabetes. Our previous experiments revealed the ability of low-weight NGF mimetic, GK-2, to reduce hyperglycaemia in a model of advanced diabetes. The increase in DNA damage in advanced diabetes was repeatedly reported, while there were no data about DNA damage in the initial diabetes.

Aim: The study aimed to establish whether DNA damage occurs in initial diabetes and whether GK-2 is able to overcome the damage.

Methods: The early-stage diabetes was modelled in Balb/c mice by streptozotocin (STZ) (130 mg/kg, i.p.). GK-2 was administered at a dose of 0.5 mg/kg, i.p., subchronically. The evaluation of DNA damage was performed using the alkaline comet assay; the percentage of DNA in the tail (%TDNA) and the percentage of the atypical DNA comets (“ghost cells”) were determined.

Results: STZ at this subthreshold dose produced a slight increase in glycemia and MDA. Meanwhile, pronounced DNA damage was observed, concerning mostly the percentage of “ghost cells” in the pancreas, the liver and kidneys. GK-2 attenuated the degree of hyperglycaemia and reduced the % of “ghost cells” and %TDNA in all the organs examined; this effect continued after discontinuation of the therapy.

Conclusion: Early-stage diabetes is accompanied by DNA damage, manifested by the increase of “ghost cells” percentage. The severity of these changes significantly exceeds the degree of hyperglycaemia and MDA accumulation. GK-2 exerts an antihyperglycaemic effect and attenuates the degree of DNA damage. Our results indicate that the comet assay is a highly informative method for search of antidiabetic medicines.

Keywords: DNA comet, “ghost cells”, early-stage diabetes, GK-2, NGF, PI3K/Akt, STZ.

Graphical Abstract

[1]
Cho, N.H. Executive summary, 8th ed; International Diabetes Federations IDF Diabetes Atlas, 2017. www.diabetesatlas.org
[2]
Levi-Montalcini, R. The nerve growth factor 35 years later. Science, 1987, 237(4819), 1154-1162.
[http://dx.doi.org/10.1126/science.3306916] [PMID: 3306916]
[3]
Yamamoto, M.; Sobue, G.; Yamamoto, K.; Terao, S.; Mitsuma, T. Expression of mRNAs for neurotrophic factors (NGF, BDNF, NT-3, and GDNF) and their receptors (p75NGFR, trkA, trkB, and trkC) in the adult human peripheral nervous system and nonneural tissues. Neurochem. Res., 1996, 21(8), 929-938.
[http://dx.doi.org/10.1007/BF02532343] [PMID: 8895847]
[4]
Paris, M.; Tourrel-Cuzin, C.; Plachot, C.; Ktorza, A. Review: pancreatic beta-cell neogenesis revisited. Exp. Diabesity Res., 2004, 5(2), 111-121.
[http://dx.doi.org/10.1080/15438600490455079] [PMID: 15203882]
[5]
Pierucci, D.; Cicconi, S.; Bonini, P.; Ferrelli, F.; Pastore, D.; Matteucci, C.; Marselli, L.; Marchetti, P.; Ris, F.; Halban, P.; Oberholzer, J.; Federici, M.; Cozzolino, F.; Lauro, R.; Borboni, P.; Marlier, L.N. NGF-withdrawal induces apoptosis in pancreatic beta cells in vitro. Diabetologia, 2001, 44(10), 1281-1295.
[http://dx.doi.org/10.1007/s001250100650] [PMID: 11692177]
[6]
Gezginci-Oktayoglu, S.; Karatug, A.; Bolkent, S. Nerve growth factor neutralization suppresses β-cell proliferation through activin A and betacellulin. Pancreas, 2015, 44(2), 243-249.
[http://dx.doi.org/10.1097/MPA.0000000000000243] [PMID: 25401376]
[7]
Chaldakov, G. The metabotrophic NGF and BDNF: an emerging concept. Arch. Ital. Biol., 2011, 149(2), 257-263.
[PMID: 21701997]
[8]
Faradji, V.; Sotelo, J. Low serum levels of nerve growth factor in diabetic neuropathy. Acta Neurol. Scand., 1990, 81(5), 402-406.
[http://dx.doi.org/10.1111/j.1600-0404.1990.tb00984.x] [PMID: 2375241]
[9]
Vidaltamayo, R.; Mery, C.M.; Angeles-Angeles, A.; Robles-Díaz, G.; Hiriart, M. Expression of nerve growth factor in human pancreatic beta cells. Growth Factors, 2003, 21(3-4), 103-107.
[http://dx.doi.org/10.1080/08977190310001629566] [PMID: 14708938]
[10]
Gudasheva, T.A.; Ostrovskaya, R.U.; Seredenin, S.B. Novel Technologies for Dipeptide Drugs Design and their Implantation. Curr. Pharm. Des., 2018, 24(26), 3020-3027.
[http://dx.doi.org/10.2174/1381612824666181008105641] [PMID: 30295186]
[11]
Gudasheva, T.A.; Povarnina, P.Yu.; Antipova, T.A.; Seredenin, S.B. A Novel Dimeric Dipeptide Mimetic of the Nerve Growth Factor Exhibits Pharmacological Effects upon Systemic Administration and Has No Side Effects Accompanying the Neurotrophin Treatment. Neurosci. Med., 2014, 5, 101-108.
[http://dx.doi.org/10.4236/nm.2014.52013]
[12]
Gudasheva, T.A.; Povarnina, P.Yu.; Antipova, T.A.; Firsova, Y.N.; Konstantinopolsky, M.A.; Seredenin, S.B. Dimeric dipeptide mimetics of the nerve growth factor Loop 4 and Loop 1 activate TRKA with different patterns of intracellular signal transduction. J. Biomed. Sci., 2015, 22, 106.
[http://dx.doi.org/10.1186/s12929-015-0198-z] [PMID: 26642930]
[13]
Ostrovskaya, R.U.; Yagubova, S.S. Common mechanisms underlying the pathogenesis of Alzheimer’s disease and diabetes: ways of pharmacological correction. Psychiatry, 2014, 1(61), 35-43.
[14]
Ostrovskaya, R.U.; Ivanov, S.V.; Ozerova, I.V. The Concept of Similarity between Pancreatic β-Cells and Neurons: Pharmacological Aspects. Eksp. Klin. Farmakol., 2017, 80(9), 20-27.
[15]
Polak, M.; Scharfmann, R.; Seilheimer, B.; Eisenbarth, G.; Dressler, D.; Verma, I.M.; Potter, H. Nerve growth factor induces neuron-like differentiation of an insulin-secreting pancreatic beta cell line. Proc. Natl. Acad. Sci. USA, 1993, 90(12), 5781-5785.
[http://dx.doi.org/10.1073/pnas.90.12.5781] [PMID: 8516328]
[16]
Bathina, S.; Das, U.N. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci., 2015, 11(6), 1164-1178.
[http://dx.doi.org/10.5114/aoms.2015.56342] [PMID: 26788077]
[17]
Seredenin, S.B.; Gudasheva, T.A.; Ostrovskaya, R.U.; Povarnina, P.Y.; Ozerova, I.V. Small molecules with NGF-like activity and antidiabetic properties. R.U. Patent 2613314 C2 2017. 11March 15;
[18]
Wajchenberg, B.L. beta-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev., 2007, 28(2), 187-218.
[http://dx.doi.org/10.1210/10.1210/er.2006-0038] [PMID: 17353295]
[19]
Butler, A.E.; Janson, J.; Bonner-Weir, S.; Ritzel, R.; Rizza, R.A.; Butler, P.C. β-Cell Deficit and Increased -Cell Apoptosis in Humans With Type 2 Diabetes pancreatic β-cells. Diabetes, 2003, 52(1), 102-110.
[http://dx.doi.org/10.2337/diabetes.52.1.102] [PMID: 12502499]
[20]
Rochette, L.; Zeller, M.; Cottin, Y.; Vergely, C. Diabetes, oxidative stress and therapeutic strategies. Biochim. Biophys. Acta, 2014, 1840(9), 2709-2729.
[http://dx.doi.org/10.1016/j.bbagen.2014.05.017] [PMID: 24905298]
[21]
Kushwaha, S.; Vikram, A.; Trivedi, P.P.; Jena, G.B. Alkaline, Endo III and FPG modified comet assay as biomarkers for the detection of oxidative DNA damage in rats with experimentally induced diabetes. Mutat. Res., 2011, 726(2), 242-250.
[http://dx.doi.org/10.1016/j.mrgentox.2011.10.004] [PMID: 22015262]
[22]
Tatsch, E.; Bochi, G.V.; Piva, S.J.; De Carvalho, J.A.; Kober, H.; Torbitz, V.D.; Duarte, T.; Signor, C.; Coelho, A.C.; Duarte, M.M.; Montagner, G.F.; Da Cruz, I.B.; Moresco, R.N. Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetes. Mutat. Res., 2012, 732(1-2), 16-20.
[http://dx.doi.org/10.1016/j.mrfmmm.2012.01.004] [PMID: 22285873]
[23]
Milic, M.; Frustaci, A.; Del Bufalo, A.; Sánchez-Alarcón, J.; Valencia-Quintana, R.; Russo, P.; Bonassi, S. DNA damage in non-communicable diseases: A clinical and epidemiological perspective. Mutat. Res., 2015, 776, 118-127.
[http://dx.doi.org/10.1016/j.mrfmmm.2014.11.009] [PMID: 26255943]
[24]
Sekkin, S.; İpek, E.D.; Boyacioglu, M.; Kum, C.; Karademir, Ü.; Yalinkilinç, H.S.; Ak, M.O.; Başaloğlu, H. DNA protective effects of melatonin on oxidative stress in streptozotocin - induced diabetic rats. Turk. J. Biol., 2015, 39, 932-940.
[http://dx.doi.org/10.3906/biy-1507-55]
[25]
El-Rahim, A.H.; Abd-Elmoneim, O.M.; Hafiz, N.A. Assessment of antigenotoxic effect of nanoselenium and metformin on diabetic rats. Jordan J. Biol. Sci., 2017, 3, 159-165.
[26]
Toğay, V.A.; Sevimli, T.S.; Sevimli, M.; Çelik, D.A.; Özçelik, N. DNA damage in rats with streptozotocin-induced diabetes; protective effect of silibinin. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2018, 825, 15-18.
[http://dx.doi.org/10.1016/j.mrgentox.2017.11.002] [PMID: 29307371]
[27]
Collins, A.R.; Raslová, K.; Somorovská, M.; Petrovská, H.; Ondrusová, A.; Vohnout, B.; Fábry, R.; Dusinská, M. DNA damage in diabetes: correlation with a clinical marker. Free Radic. Biol. Med., 1998, 25(3), 373-377.
[http://dx.doi.org/10.1016/S0891-5849(98)00053-7] [PMID: 9680185]
[28]
Salem, S.I.; El-Toukhy, S.E.; El-Saeed, G.S.; El-Wassefe, M. Correlation of DNA damage in type 2 diabetes to glycemic control. Egyptian J of Hospital Med, 2012, 48, 472-482.
[29]
Durnev, A.D.; Zhanataev, A.K.; Shreder, O.V.; Seredenina, V.S. Genotoxic events and diseases. Mol. Med., 2013, 3, 3-19.
[30]
Umeno, A.; Biju, V.; Yoshida, Y. In vivo ROS production and use of oxidative stress-derived biomarkers to detect the onset of diseases such as Alzheimer’s disease, Parkinson’s disease, and diabetes. Free Radic. Res., 2017, 51(4), 413-427.
[http://dx.doi.org/10.1080/10715762.2017.1315114] [PMID: 28372523]
[31]
Rubinstein, M.R.; Genaro, A.M.; Wald, M.R. Differential effect of hyperglycaemia on the immune response in an experimental model of diabetes in BALB/cByJ and C57Bl/6J mice: participation of oxidative stress. Clin. Exp. Immunol., 2013, 171(3), 319-329.
[http://dx.doi.org/10.1111/cei.12020] [PMID: 23379439]
[32]
Hayashi, K.; Kojima, R.; Ito, M. Strain differences in the diabetogenic activity of streptozotocin in mice. Biol. Pharm. Bull., 2006, 29(6), 1110-1119.
[http://dx.doi.org/10.1248/bpb.29.1110] [PMID: 16755002]
[33]
Watcho, P.; Stavniichuk, R.; Tane, P.; Shevalye, H.; Maksimchyk, Y.; Pacher, P.; Obrosova, I.G. Evaluation of PMI-5011, an ethanolic extract of Artemisia dracunculus L., on peripheral neuropathy in streptozotocin-diabetic mice. Int. J. Mol. Med., 2011, 27(3), 299-307.
[PMID: 21225225]
[34]
Leonard, C.E.; Han, X.; Brensinger, C.M.; Bilker, W.B.; Cardillo, S.; Flory, J.H.; Hennessy, S. Comparative risk of serious hypoglycemia with oral antidiabetic monotherapy: A retrospective cohort study. Pharmacoepidemiol. Drug Saf., 2018, 27(1), 9-18.
[http://dx.doi.org/10.1002/pds.4337] [PMID: 29108130]
[35]
Moore, K.; Roberts, L.J., II Measurement of lipid peroxidation. Free Radic. Res., 1998, 28(6), 659-671.
[http://dx.doi.org/10.3109/10715769809065821] [PMID: 9736317]
[36]
Azqueta, A.; Gutzkow, K.B.; Brunborg, G.; Collins, A.R. Towards a more reliable comet assay: optimising agarose concentration, unwinding time and electrophoresis conditions. Mutat. Res., 2011, 724(1-2), 41-45.
[http://dx.doi.org/10.1016/j.mrgentox.2011.05.010] [PMID: 21645630]
[37]
Zhanataev, A.K.; Anisina, E.A.; Chayka, Z.V.; Miroshkina, I.A.; Durnev, A.D. The phenomenon of atypical DNA comets. Cell and Tissue Biology 11(4):286–292. Tsitologiia, 2017, 59(3), 163-168.
[PMID: 30183153]
[38]
Møller, P.; Loft, S. Statistical analysis of comet assay results. Front. Genet., 2014, 5, 292.
[PMID: 25221569]
[39]
Ostrovskaya, R.U.; Yagubova, S.S.; Gudasheva, T.A.; Seredenin, S.B. Low-Molecular-Weight NGF Mimetic Corrects the Cognitive Deficit and Depression-like Behavior in Experimental Diabetes. Acta Naturae, 2017, 9(2), 94-102.
[http://dx.doi.org/10.32607/20758251-2017-9-2-94-102] [PMID: 28740732]
[40]
Damasceno, D.C.; Netto, A.O.; Iessi, I.L.; Gallego, F.Q.; Corvino, S.B.; Dallaqua, B.; Sinzato, Y.K.; Bueno, A.; Calderon, I.M.; Rudge, M.V. Streptozotocin-induced diabetes models: pathophysiological mechanisms and fetal outcomes. BioMed Res. Int., 2014. 2014819065
[http://dx.doi.org/10.1155/2014/819065] [PMID: 24977161]
[41]
Zabrodina, V.V.; Shreder, E.D.; Shreder, O.V.; Durnev, A.D.; Seredenin, S.B. Effect of Afobazole and Betaine on DNA Damage in Placental and Embryonic Tissues of Rats with Experimental Streptozocin Diabetes. Bull. Exp. Biol. Med., 2015, 159(6), 757-760.
[http://dx.doi.org/10.1007/s10517-015-3068-5] [PMID: 26519266]
[42]
Zabrodina, V.V.; Shreder, O.V.; Shreder, E.D.; Durnev, A.D. Effect of Afobazole and Betaine on Cognitive Disorders in the Offspring of Rats with Streptozotocin-Induced Diabetes and Their Relationship with DNA Damage. Bull. Exp. Biol. Med., 2016, 161(3), 359-366.
[http://dx.doi.org/10.1007/s10517-016-3414-2] [PMID: 27502535]
[43]
Haligur, M.; Topsakal, S.; Ozmen, O. Early degenerative effects of diabetes mellitus on pancreas, liver, and kidney in rats: an immunohistochemical study. Exp. Diabetes Res., 2012. 2012120645
[http://dx.doi.org/10.1155/2012/120645] [PMID: 22844268]
[44]
Volpe, C.M.O.; Villar-Delfino, P.H.; Dos Anjos, P.M.F.; Nogueira-Machado, J.A. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis., 2018, 9(2), 119.
[http://dx.doi.org/10.1038/s41419-017-0135-z] [PMID: 29371661]
[45]
Samadder, A.; Chakraborty, D.; De, A.; Bhattacharyya, S.S.; Bhadra, K.; Khuda-Bukhsh, A.R. It is possible that the signaling cascades can be taken into account in the synthesis of the syzygium jambolanum: drug-DNA interaction with calfium DNA as target. Eur J Pharm, 2011, 44(3), 207-217.
[http://dx.doi.org/10.1016/j.ejps.2011.07.012]
[46]
Gudasheva, T.A.; Antipova, T.A.; Konstantinopolsky, M.A.; Povarnina, P.Y.; Seredenin, S.B. Nerve growth factor novel dipeptide mimetic GK-2 selectively activates TrkA postreceptor signaling pathways and does not cause adverse effects of native neurotrophin. Dokl. Biochem. Biophys., 2014, 456(1), 88-91.
[http://dx.doi.org/10.1134/S1607672914030028] [PMID: 24993963]
[47]
Ye, K. PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J. Cell. Biochem., 2005, 96(3), 463-472.
[http://dx.doi.org/10.1002/jcb.20549] [PMID: 16088938]
[48]
Ahn, J.Y.; Liu, X.; Liu, Z.; Pereira, L.; Cheng, D.; Peng, J.; Wade, P.A.; Hamburger, A.W.; Ye, K. Nuclear Akt associates with PKC-phosphorylated Ebp1, preventing DNA fragmentation by inhibition of caspase-activated DNase. EMBO J., 2006, 25(10), 2083-2095.
[http://dx.doi.org/10.1038/sj.emboj.7601111] [PMID: 16642037]
[49]
Dickson, L.M.; Rhodes, C.J. Pancreatic β-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt? Am. J. Physiol. Endocrinol. Metab., 2004, 287(2), E192-E198.
[http://dx.doi.org/10.1152/ajpendo.00031.2004] [PMID: 15271644]
[50]
Ostrovskaya, R.U.; Yagubova, S.S.; Gudasheva, T.A.; Seredenin, S.B. Antidiabetic Properties of Low-Molecular-Weight BDNF Mimetics Depend on the Type of Activation of Post-Receptor Signaling Pathways. Bull. Exp. Biol. Med., 2018, 164(6), 734-737.
[http://dx.doi.org/10.1007/s10517-018-4069-y] [PMID: 29658083]
[51]
Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol., 2000, 10(3), 381-391.
[http://dx.doi.org/10.1016/S0959-4388(00)00092-1] [PMID: 10851172]