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

[ Vol. 20 , Issue. 3 ]

Author(s):

Svetlana Yagubova, Aliy Zhanataev, Rita Ostrovskaya*, Еlena Anisina, Тatiana Gudasheva, Аndrey Durnev and Sergey Seredenin   Pages 453 - 463 ( 11 )

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.

Affiliation:

Laboratory of Psychopharmacology, FSBI “Zakusov Institute of Pharmacology”, Moscow, Laboratory of pharmacology and mutagenesis, FSBI “Zakusov Institute of Pharmacology”, Moscow, Laboratory of Psychopharmacology, FSBI “Zakusov Institute of Pharmacology”, Moscow, Laboratory of pharmacology and mutagenesis, FSBI “Zakusov Institute of Pharmacology”, Moscow, Department of Medicinal Chemistry, FSBI “Zakusov Institute of Pharmacology”, Moscow, Laboratory of Drug Toxicology, FSBI “Zakusov Institute of Pharmacology”, Moscow, Department of Pharmacogenetics, FSBI “Zakusov Institute of Pharmacology”, Moscow

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