Rita U Ostrovskaya

Russian Academy of Medical Sciences | RAMS · Institute of Pharmacology, Laboratory Psychopharmacology

It was previously established that the original dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), has a pronounced neuroprotective effect in vitro at concentrations of 10-5-10-12 М. In the present study, experiments on the streptozotocin-induced diabetes model in C57Bl/6 mice...

It was previously established that the original dipeptide mimetic of the 4th loop of NT-3, hexamethylenediamide bis-(N-monosuccinyl-L-asparaginyl-L-asparagine) (GTS-301), has a pronounced neuroprotective effect in vitro at concentrations of 10–5–10–12 М. In the present study, experiments on the streptozotocin-induced diabetes model in C57Bl/6 mice...

Relevance. To conduct a preclinical evaluation of the effectiveness of antidiabetic drugs, models simulating the pathogenesis and main manifestations of diabetes mellitus (DM) in humans are needed. The streptozotocin (STZ) model, which has received the most widespread use in the experiment, does not allow reproducing the stepwise multifactorial dev...

Настоящее изобретение относится к области биотехнологии, конкретно к новым биологически активным молекулам, содержащим дипептиды, и может быть использовано в медицине. Изобретение раскрывает возможность получения соединений, характеризующихся общей формулой (R-CO-L-AK-X-Asn-NH-)2(CH2)6, где R = НООС-(СН2)2-, или НООС-(СН2)3-, или НО-(СН2)3-, AK = G...

The effect of low-molecular-weight mimetics of NGF and BDNF (GK-2 and GSB-214 in a dose 0.5 mg/kg, respectively) on malondialdehyde content and activity of an antioxidant defense enzyme glutathione peroxidase was studied in experiments on C57BL/6 mice with streptozotocin-induced diabetes. An increase in the malondialdehyde content indicating enhanc...

Noopept (NP) is a proline-containing dipeptide with nootropic and neuroprotective properties. We have previously shown that NP significantly increased the frequency of spontaneous IPSCs in hippocampal CA1 pyramidal cells mediated by the activation of inhibitory interneurons in stratum radiatum. The cholinergic system plays an important role in the...

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 abdomi...

A low-molecular-weight nerve growth factor mimetic, compound GK-2 (bis-(N-monosuccinyl- L-glutamyl-L-lysine)hexamethylenediamide) that previously demonstrated antidiabetic activity in rats with streptozotocin-induced type 2 diabetes mellitus was studied on the model of diabetic neuropathy. It was found that in 8 weeks after diabetes mellitus develo...

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 s...

Experimental results for the new nerve growth factor (NGF) mimetic GK-2 [bis-(N-monosuccinyl-L-glutamyl-L-lysine)hexamethylenediamide] administered perorally toWistar rats in a streptozotocin-induced type 2 diabetes mellitus model are reported. The antihyperglycemic activity of GK-2 was determined in a dose range from 1 to 10 mg/kg. The most pronou...

Previous in vitro and in vivo studies revealed the neuroprotective effect of anxiolytic Afobazole. Based on similarities in the regulation of functions of neurons and β cells, we studied the effect of Afobazole on streptozotocin (STZ) model of type 2 diabetes in Wistar rats. Immunohistochemical analysis showed that the decrease in the number of β c...

In our previous studies on the streptozotocin model of diabetes we hypothesized that activation of the PI3K/Akt signaling pathway is essential for the realization of the antidiabetic effect of low-molecular-weight NGF and BDNF mimetics. Here we analyze the effect of a specific PI3K/Akt pathway inhibitor (LY 294002) on the antidiabetic effect of the...

Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for precl...

We present here results of studies of the antidiabetic activity of compound GK-2 (bis-(N-monosuccinyl-glutamyl-L-lysine) hexamethylenediamide), an NGF mimetic, in a model of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Two-week prophylactic courses of oral GK-2 did not decrease blood glucose levels in healthy animals but reduces...

In experiments on BALB/c mice, prediabetes was modeled by administration of streptozotocin in a dose of 130 mg/kg. DNA damage was assessed by the method of DNA comets. Noopept (0.5 mg/kg intraperitoneally) was administered for 14 days before and for 6, 13, or 14 days after streptozotocin administration. Despite moderate hyperglycemia and increased...

The nootropic agents noopept and piracetam alter the amplitudes of acetylcholine-induced influx currents (ACh currents) in command neurons in the common snail. Both compounds have cholinopositive activity. The dose curve of the actions of noopept is bell-shaped, while the piracetam dose-response curve in the range of physiological concentrations sh...

Experiments on Wistar rats using a model of type 2 diabetes induced by streptozotocin (STZ) at a dose of 40 mg/kg addressed the effects of the proline-containing dipeptide noopept (the ethyl ester of N-phenylacetyl-L-prolylglycine) on nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents. Untreated diabetic rats showed 59%...

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 initi...

We investigated the cytoprotective effect of a novel low-molecular-weight NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine), on pancreatic β-cells. The neuroprotective effect of GK-2 had been previously shown to be associated with selective activation of the PI3K/Akt signaling pathway. In this study, rats with streptoz...

Effects of Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) on the relative level of proliferation marker Ki-67 and cell cycle parameters were studied in HEK293 and SH-SY5Y cell lines. The previously established multifactorial mechanism of action of the drug includes enhancement of neurotrophin NGF and BDNF expression and increase in HIF-1 acti...

We studied the effect of the neuroprotective dipeptide drug noopept on the level of biogenic amines in the retina during the thrombosis of its vessels in experiments with male chinchilla rabbits. Ischemic lesion of the retina was modeled by intravenous administration of rose bengal at a dose of 40 mg/kg body weight followed by 10-min transpupillary...

We studied antidiabetic effects and cytoprotective activity of two lithium salts (lithium chloride and lithium carbonate) on the model of streptozotocin-induced diabetes mellitus type 2 in Wistar rats. Using the method of β-cells detection with antibodies to insulin, we demonstrated that streptozotocin reduced the number of β-cells and impaired the...

The article is an overview of author's data obtained in the framework of the project "The Creation of dipeptide preparations" at the V.V. Zakusov Institute of Pharmacology, Moscow, Russia. Advantages of dipeptides over longer peptides consist in that they are orally active owing to higher stability and ability to penetrate biological barriers due t...

Using the streptozotocin model of type 2 diabetes mellitus in Wistar rats, we compared antidiabetic activity of anxiolytic Afobazole with that of metformin. Afobazole in a dose of 10 mg/kg reduced streptozotocin-induced hyperglycemia and polyphagia and prevented accumulation of malonic dialdehyde, being not inferior to metformin in a dose of 300 mg...

Reduced proliferation and enhanced apoptosis of β cells in diabetes mellitus are associated with a deficiency of brain-derived neurotrophic factor (BDNF). Low-molecular weight compounds similar to different BDNF loops were synthesized at the V. V. Zakusov Research Institute of Pharmacology. They produce a potentiating effect on TrkB phosphorylation...

We studied the influence of the neuroprotective dipeptide drug noopept on the state of the retina during thrombosis of its vessels in an experiment with male chinchilla rabbits. The pathology was modeled by intravenous injection of rose Bengal at a dose of 40 mg/kg followed by transpupillary focal illumination with white light of the temporal vascu...

Background: Noopept (N-phenylacetyl-L-prolyl-glycine ethyl ester) is approved in Russia as cognition enhancer. To establish the mechanisms responsible for Noopet's neuroptopic effects we have focused on the HIF-1-dependent pathway. Hypoxia-inducible growth factor-1 (HIF-1) is the master regulator of cellular and tissue adaptive responses to low oxy...

The effect of proline-containing dipeptide Noopept (N-phenylacetyl ethyl ester-L-prolylgly- cine ethyl ester) on the content of NGF and BDNF in the pancreas and liver was studied in experiments on Wistar rats using the model of diabetes 2 induced by streptozotocin (STZ) at a dose of 40 mg/kg. In the group of active control (STZ followed by saline a...

Введение. Исходя из литературных данных о роли оксидативного и нитрозативного стресса в патогенезе сахарного диабета (СД) и наличии собственных данных об антидиабетическом эффекте ноотропного и нейропротективного дипептида Ноопепт (этиловый эфир N-фенилацетил-L-пролилглицина), представляло интерес воспроизвести трансляциионную модель СД и изучить в...

Based on the comorbidity of diabetes, depression, and dementia and recognizing that a deficiency of the nerve growth factor (NGF) is involved in all of these kinds of pathologies, we studied the effect of the mimetic of dimeric dipeptide NGF loop 4, GK-2, on a model of streptozotocin-induced type 2 diabetes in C57Bl/6 mice. GK-2 [hexamethylenediami...

Previously designed cyclo-L-prolylglycine (CPG), a peptide prototype of piracetam, was discovered as an endogenous compound in rat brain and exhibited nootropic and anxiolytic properties. N-Phenylacetylglycyl-L-proline ethyl ester (GZK-111) was synthesized in the present work. It was established that GZK-111 converted to CPG and possessed nootropic...

Deficiency of neurotrophins is known to be one of the major pathogenetic factors of reduced proliferation and enhanced apoptosis of pancreatic P-cells during diabetes. The ability of nerve growth factor (NGF) to maintain the functioning of 0-cells and stimulate insulin secretion suggests that NGF may be useful in the treatment of type 2 diabetes. U...

Specific features of the ontogenetic and pathophysiological similarity of neurons and pancreatic β-cells are analyzed. Common mechanisms of the development of neurodegenerative diseases and diabetes mellitus open new opportunities for the correction of these pathological states by substances attenuating the intensity of oxidative stress and the def...

Literature data concerning modern state-of-the-art in genetic and chemical modeling of type 2 diabetes mellitus are analyzed. Increasing incidence of diabetes, the lack of medicines effectively protecting the secretory function of pancreatic b-cells, and pronounced side effects of known antidiabetic drugs stimulate the search for new effective and...

Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) revealed wide spectrum of neuroprotective effects and one of the mechanisms underlying this neuroprotection is the increase of Nerve Growth Factor (NGF) and Brain-derived Neurotrophic Factor (BDNF) expression in hippocampus and hypothalamus. Features of neurons and pancreatic beta-cells similarit...

Effect of noopept (N-phenylacetyl-prolylglycine ethyl ester) on viability of neurons exposed to neurotoxic action of glutamic acid (5 mM) was studied in vitro in immortalized mouse hippocampal HT-22 neurons. Noopept added to the medium before or after glutamic acid improved neuronal survival in a concentration range of 10–11-10–5 M. Comparison of t...

We studied the effect of thrombosis of retina vessels on the development of glutamate excitotoxicity in chinchilla rabbits. Thrombosis was induced by administration of Bengal rose dye at a dose of 40 mg/kg into the auricular vein of the animals followed by focal lighting with white light. Lighting was performed for 10 min on average at the temporal...

This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (...

Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration...

Background Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxic...

Experiments on adult Wistar rats with streptozotocin-induced diabetes showed that antihyperglycemic activity of an original nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) is more pronounced under conditions of oral application than after intraperitoneal injection. These data provided a basis for studying the...

Developing diabetes was modeled on adult male Wistar rats by repeated intraperitoneal injections of streptozotocin in a subdiabetogenic dose of 30 mg/kg for 3 days. Proline-containing dipeptide drug Noopept or a standard diabetic drug dipeptidyl peptidase-4 inhibitor sitagliptin was administered per os in a dose of 5 mg/kg before each injection of...

The effect of an original dimeric dipeptide NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine, designed on the basis of the beta-turn of the 4th NGF loop) on the hemostasis and fibrinolysis was studied in intact and diabetic Wistar rats in various periods of disorder development. Model diabetes was induced by single str...

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 ani...

The effect of dipeptidal neurotensine mimetic, N-caproyl-L-prolyl-L-tyrosine methyl ester (GZR-123, Dilept) and its main metabolite N-caproyl-L-prolyl-L-tyrosine (GZR-125) was evaluated at novel objects recognition test (NOR) in the male outbred rats. NOR was chosen from many cognitive test as those involving the selective action on the attention a...

The effect of a new dimeric dipeptide mimetic GK-2 of the loop-4 human NGF (hexamethylendiamide-bis-N-monosuccinyl-glycil-L-lysine) was investigated for the first time on the dynamics of hyperglycemia and body weight loss caused in Wistar rats by streptozotocin (45 mg/kg i.p.) Prophylactic (2 weeks before streptozotocin) daily administration combin...

76 An antidiabetic effect of the new nerve growth fac� tor (NGF) dipeptide mimetic GK�2 has been shown in rats with streptozotocininduced diabetes. The pep� tide has a significant antihyperglycemic effect in the course of treatment: intraperitoneal injection at a dose of 0.5 mg/kg for two weeks before and four weeks after the toxin injection. GK�2...

We studied the effects of new nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) in various dosage regimens on the dynamics of glycemia, body weight, and pain sensitivity in rats receiving diabetogenic toxin streptozotocin. In experimental diabetic rats, Noopept alleviated glycemia and weight loss and normalized...

The behavioral and biochemical effects of a new dipeptide mimetic of the GK-2 nerve growth factor (NGF) have been studied on a model of chronic cerebral ischemia induced by permanent common carotid artery occlusion in rats. It is established that subchronic intraperitoneal injections of GK-2 (0.5 mg/kg) 4 h after surgery, followed by seven more inj...

We studied the effects of neurotensin dipeptide analog Dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) on dopamine metabolism and synthesis in the nucleus accumbens of Wistar rats. Dilept increased the levels of dopamine and its metabolites (homovanillic acid and dioxyphenylalanine) and stimulated dopamine turnover in this structure. Dilept acc...

Tridecapeptide neurotensin (NT) is known to exert the neuroleptic-like effects in case of its intracerebral administration. The group of systemically active dipeptides , acylprolyltyrosines, was constructed on the background of NT. Methyl ester of N-caproyl-L-prolyl-L-tyrosine (Dilept) was chosen for further development. The paper is dealing with m...

A series of systemically active N�acylprolyltyrosines was constructed based on the structure of endogenous neuroleptic�like tridecapeptide neurotensin that exhibits activity on intracerebral administra� tion. Among these dipeptides, N�caproyl�L�prolyl�L�tyrosine methyl ester (Dilept) was chosen for further development. The paper briefly describes t...

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under condi...

The influence of dilept (GZR-123, N-caproyl-L-prolyl-L-tyrosine methyl ester)--a dipeptide analog of neurotensin (NT)--on extracellular concentration of glutamate, gamma-aminobutyric acid (GABA) and homovanillic acid (HVA) in n. accumbens of Wistar rats has been studied. By means of microdialysis, it was shown that dilept increases the concentratio...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Streptozotocin-intracerebroventricularly treated rats are proposed as an experimental model of sporadic Alzheimer disease (AD). Diabetogenic toxin streptozotocin (STZ) administered in both cerebral ventricles in a dose of 3 mg/kg decreases the expression of NGF and BDNF mainly in the hippocampus and increases the content of malonic dialdehyde (MDA)...

The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introducti...

The antipsychotic properties of dilept, a new drug representing substituted dipeptide based on a beta-rotational structure of the main metabolite of endogenous neuroleptic NT8-13, have been studied using the test for prestimulus inhibition (PSI) of the acoustic startle reflex in rats. It is established that dilept eliminates the PSI deficiency caus...

The metabolism and pharmacokinetics of a new neurotensine-derived dipeptide drug dilept (N-caproyl-L-prolyltyrosine methyl ester) and its tentative metabolites after intravenous and peroral administration of the parent drug and its tabletized form in rats have been studied by HPLC-ESI(-)-MS/MS method. It is established that unchanged dilept (detect...

Male C57BL/6J, BALB/c, and DBA/2J mice showed differences in their abilities to perform two cognitive tests. C57BL/6J mice had good learning ability and memory trace retention (at 10 days) in a simplified Morris maze, while BALB/c mice had low levels of memory trace retention and DBA/2J mice had low learning ability in this test. I.p. administratio...

We studied the effect of original dipeptide preparation Noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) with nootropic and neuroprotective properties on the expression of mRNA for neurotropic factors NGF and BDNF in rat hippocampus. Expression of NGF and BDNF mRNA in the cerebral cortex and hippocampus was studied by Northern blot ana...

Antiamnesic activity of Noopept was studied on the original three-way model of conditioned passive avoidance response, which allows studying spatial component of memory. Cholinoceptor antagonists of both types (scopolamine and mecamylamine) decreased entry latency and reduced the probability for selection of the safe compartment. Noopept abolished...

Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide,...

We have performed a comparative study of the content of glutamate (Glu), aspartate (Asp), taurine (Tau), glycine (Gly) and gamma-amino-butyric acid (GABA) in the cortex, hippocampus, and striatum of the DBA/2J, Balb/c and C57BL/6 mice brain. The levels of Glu, Tau and GABA in DBA/2J hippocampus was lower than those in other experimental strains. Th...

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces wer...

The antioxidative activity of the nootropic dipeptide Noopept (the ethyl ether of N-phenylacetyl-L-prolyglycine, GVS-111) was studied on a model of Fe2+-induced chemiluminescence (CL) of serum lipoproteins from healthy human donors in vitro. Efficiency of the following antioxidant agents has been compared: Noopept, pyracetam (the non-peptide protot...

Genotype-dependent behavioral effects were demonstrated in BALB/c, C57BL/6J [Russian character: see text] DBA/2J mice after injections of nootropic drug Noopept. In an elevated plus maze, drug administration induced an increase in the number of enterings into bright arms in BALB/c mice, whereas the opposite effect was observed in C57BL/6J. After th...

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairm...

Noopept, a peptide analog of piracetam, enhanced phagocytic activity of mouse peritoneal macrophages, stimulated humoral and cellular immune response to various antigens, and markedly increased spontaneous proliferative activity of splenocytes. In animals with secondary immune deficiency caused by cyclophosphamide, noopept exhibited immunocorrector...

The level of spontaneous and K+-stimulated release of endogenous glutamate was studied in experiments on slices of brain cortex of Wistar rats. Pronounced spontaneous release of the neuromediator and its increase under conditions of stimulation were registered by high-performance liquid chromatography with electrochemical detection. The effect of t...

The effect of original nootropic preparation Noopept on learning and long-term memory was studied with BALB/c mice. Scopolamine (1 mg/kg) impaired long-term memory trace, while Noopept (0.5 mg/kg) had no significant effect. Noopept completely prevented the development of cognitive disorders induced by scopolamine (blockade of muscarinic cholinergic...

Dilept (GZR-123, N-caproyl-L-prolyl-L-tyrosine methyl ester), designed and synthesized at the Zakusov Institute of Pharmacology, was chosen as one of the most effective compounds from a series of N-acylprolyltyrosine derivatives having common pharmacophores with beta-turn of neurotensin (NT(8-13)) and repeating the structure of a nonpeptide prototy...

The pharmacokinetics of noopept, a dipeptide drug possessing nootropic and neuroprotective properties, were evaluated in rats The pharmacokinetics of noopept, a dipeptide drug possessing nootropic and neuroprotective properties, were evaluated in rats after the intravenous administration of its novel formulation for injections prepared using lyophi...