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

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

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 20 , Issue 3 , 2020

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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.

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VOLUME: 20
ISSUE: 3
Year: 2020
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DOI: 10.2174/1871530319666190806115623
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