Antidiabetic activity of a novel dipeptide mimetic of nerve growth factor

Povarnina, P. Yu.; Ozerova, I. V.; Ostrovskaya, R. U.; Gudasheva, T. A.; Seredenin, S. B.

doi:10.1134/s001249661302004x

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…Dipeptide GK-2 exhibits low toxicity (LD 50 = 714 mg/kg upon intravenous administration to male mongrel mice) and shows none of the major side effects typical of NGF. It does not reduce the pain threshold (at doses of 0.5–2 mg/kg i/p in a tail flick test after thermal stimulation, water temperature of 55°C) [24] and does not cause weight loss upon chronic administration to rats (0.5 mg/kg, i/p) [25]. …”

Section: Introductionmentioning

confidence: 99%

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

et al. 2013

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Dipeptide mimetic of the nerve growth factor (NGF) loop 4, hexamethylenediamide bis-(N-monosuccinyl- glutamyl-lysine) (GK-2), was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology of the Russian Academy of Medical Sciences. GK-2 exhibited in vitro neuroprotective activity at nanomolar concentrations, was efficient in animal models of the Parkinson’s disease, ischemic and hemorrhagic stroke, and global cerebral ischemia at doses of 0.01–5 mg/kg (intraperitoneally) and 10 mg/kg (per os). The mnemotropic effects of subchronic intraperitoneal administration of GK-2 on rat models of the Alzheimer’s disease are described in this paper. Dipeptide GK-2 at a dose of 1 mg/kg is found to decrease the habituation deficit induced by the septo-hippocampal pathway transsection and, at a dose of 0.5 mg/kg, to significantly prevent spatial memory impairment in Morris water maze induced by intracerebral injection of streptozotocin. Thus, GK-2, an original dipeptide mimetic of NGF, acts on models of the Alzheimer’s disease upon systemic administration.

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Section: Introductionmentioning

confidence: 99%

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

et al. 2013

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“…According to this approach, a β‐turn Asp 93 ‐Glu 94 ‐Lys 95 ‐Gln 96 of the 4th NGF loop, was used to create a dipeptide mimetic called “GK‐2” 19,20 . Proceeding from the fact that GK‐2 demonstrated the ability to mimic the effects of native neurotrophin in experiments on neurons, 21,22 and that NGF deficiency plays an important role in the T2DM pathogenesis, GK‐2 was studied in the streptozotocin‐induced (STZ) diabetes model in Wistar rats 23,24 . On the model of developed T2DM (glycaemic level above 21 mmol/L), GK‐2 demonstrated a pronounced antihyperglycaemic activity, normalized the body weight dynamics, and attenuated the polyphagia and polydipsia 25 …”

Section: Introductionmentioning

confidence: 99%

“…19,20 Proceeding from the fact that GK-2 demonstrated the ability to mimic the effects of native neurotrophin in experiments on neurons, 21,22 and that NGF deficiency plays an important role in the T2DM pathogenesis, GK-2 was studied in the streptozotocin-induced (STZ) diabetes model in Wistar rats. 23,24 On the model of developed T2DM (glycaemic level above 21 mmol/L), GK-2 demonstrated a pronounced antihyperglycaemic activity, normalized the body weight dynamics, and attenuated the polyphagia and polydipsia. 25 One of the most frequently used and effective methods for modelling early glucose metabolism disorders in experiments is a high-fat diet (HFD).…”

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confidence: 99%

Low molecular weightNGFmimeticGK‐2 normalizes the parameters of glucose and lipid metabolism and exhibits a hepatoprotective effect on a prediabetes model in obese Wistar rats

Ivanov

Ostrovskaya

et al. 2022

Clin Exp Pharma Physio

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Signs of metabolic syndrome and prediabetes preceding type 2 diabetes are modelled in an experiment using a high‐fat diet (HFD). The aim of this work was to study the effect of a low molecular weight systemically active nerve growth factor mimetic, compound GK‐2 (hexamethylenediamide bis[N‐monosuccinyl‐L‐glutamyl‐L‐lysine]), on indicators of abdominal obesity, basal blood glucose level, glucose tolerance, cholesterol and triglyceride blood levels, as well as the morphological structure of the liver in male Wistar rats fed a HFD. Rats were divided into three groups: one of them received standard food (control) and two others were fed a HFD containing 45% fat, 35% carbohydrates and 20% protein, with a total caloric value of 516 kcal/100 g, over 12 weeks. Starting from the ninth week, for the next 4 weeks, one of the HFD groups was treated orally with saline whilst the other group was treated orally with GK‐2 at a dose of 5 mg/kg. GK‐2 was found to reduce the basal glycaemia level and improve glucose tolerance, as well as to reduce the blood level of cholesterol by 30% and that of triglycerides by 28% in comparison with the saline‐treated HFD animals. GK‐2 reduced the degree of abdominal obesity to the level of the healthy animals and eliminated morphological abnormalities in the liver caused by the HFD. The results of the study determine the feasibility of further GK‐2 research as a potential agent for prediabetes treatment.

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Neuroprotective Substances: Are they Able to Protect the Pancreatic Beta- Cells Too?

Ivanov

Ostrovskaya

2022

EMIDDT

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Background: Growing evidences demonstrate a close relationship between type 2 diabetes (T2D) and neurodegenerative disorders such as Alzheimer’s disease. The similarity of physiological and pathological processes, occurring in pancreatic β-cells and neurons over the course of these pathologies, allows to raise the question of the practicability of studying neuroprotective substances for their potential antidiabetic activity. Objective: This review analyzes studies of antidiabetic and cytoprotective action on pancreatic β-cells of the neuroprotective compounds that can attenuate the oxidative stress and enhance the expression of neurotrophins: low-molecular-weight NGF mimetic compound GK-2, selective anxiolytic afobazole, antidepressants lithium chloride and lithium carbonate on the rat streptozotocin model of T2D. Results: It was found that all above-listed neuroprotective substances have a pronounced antidiabetic activity. The decrease in the β-cells number, the average area of the pancreatic islets, as well as the violation of their morphological structure caused by the streptozotocin was significantly weakened by the therapy with the investigated neuroprotective substances. The extent of these morphological changes clearly correlates with the antihyperglycemic effect of these compounds. Conclusion: The presented data indicate that the neuroprotective substances attenuating the damaging effect of oxidative stress and neurotrophins deficit cannot only protect neurons but also exert their cytoprotective effect towards pancreatic β-cells. These data may provide a theoretical basis for the further study of neuroprotective drugs as potential therapeutic options for T2D prevention and treatment.

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Antidiabetic activity of a novel dipeptide mimetic of nerve growth factor

Cited by 3 publications

References 7 publications

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease

Low molecular weightNGFmimeticGK‐2 normalizes the parameters of glucose and lipid metabolism and exhibits a hepatoprotective effect on a prediabetes model in obese Wistar rats

Neuroprotective Substances: Are they Able to Protect the Pancreatic Beta- Cells Too?

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