[A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders].

Objective. To study the efficacy and tolerability of the new anxyolytic peptide selank in comparison with phenazepam. Material and methods. A comparative study of the anxiolytic effect and tolerability of selank and phenazepam was carried out in 60 patients with phobic-anxiety- and somatoform disorders (F40.2-9, F41.1-9, F45.0-1 by ICD-10) were examined. Results Pronounced anxiolytic and mild nootropic effects of selank were demonstrated. The anxiolytic effect lasted for a week after last receiving the peptide. Selank had a positive impact on the quality of life of the patients. Conclusion. The data obtained in the study extend therapeutic possibilities in the treatment of anxiety disorders.

[Antiaggregation activity of arachidonic acid conjugates with neurotropic peptides proglyprol and semax].

The influence two original derivatives of a therapeutically important peptide, bearing arachidonic acid residue with semax and proglyprol, upon platelet aggregation have been studied in vitro. It is established that both derivatives, in contrast to the parent peptide, possess moderate anti-aggregant properties and produce a dose-dependent decrease in the interplatelet interaction induced by ADP, epinephrine, and arachidonic acid within the concentration range of 0.018 - 1.8 mM. This activity was more pronounced for arachidonoylsemax in comparison with arachidonoylproglyprol.

[Effect of tripeptide Pro-Gly-Pro on rat brain transcriptome in focal ischemia].

Biologically active regulatory peptide, tripeptide Pro-Gly-Pro (PGP) was used as C-terminal fragment for peptide drugs Semax and Selank. In recent years the independent effects of PGP were observed. The question was raised, whether PGP contributes to the effects ofpeptide drugs containing PGP as a fragment. The genome-wide analysis was performed to investigate the influence of PGP on the transcriptome of ischemic rat brain cortex tissues. The gene expression alterations caused by the action of the tripeptide PGP were compared with the gene expression of the control group "ischemia" at 3 and 24 h after permanent occlusion of left middle cerebral artery. The altered expression was detected for 29 genes at 3 h and 57--at 24 h. The proteins encoded by these genes have variety of functions: cytokines, transport proteins, transcription factors, transmembrane receptors, etc. Biological processes, which are related to the genes with altered expression, were distinguished. The influence of PGP on the diversity of biological processes in different systems of the organism is demonstrated for the first time. The process "Immune response" was the most statistically notable at 24 h after occlusion. The expression of the immune system genes was predominately down regulated.

[Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment].

The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4-6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax.

[Correction of impairments in functions of anticoagulation and insular systems of an organism by the regulatory peptide Leu-Pro-Gly-Pro].

It has been established that fivefold intranasal administration of the peptide Leu-Pro-Gly-Pro (1 mg/kg) to rats with developing refractory hyperglycemia leads to restoration and normalization of the functions of anticoagulation and insular systems. In the blood of experimental animals, there was a decrease in the sugar level and platelet aggregation and an increase in anticoagulant and all kinds of fibrinolytic (total, enzymatic, non-enzymatic, Hageman-dependent) activity.

[The effect of semax and its C-end peptide PGP on Vegfa gene expression in the rat brain during incomplete global ischemia].

Vascular endothelial growth factor (VEGFA) is a hypoxia-inducible signal glycoprotein. VEGFA causes vascular endothelial cell growth and proliferation, that leads to the regeneration of vascular network in brain regions damaged by ischemia. However, this protein is involved in processes of inflammation and edema in early stages of ischemia. Synthetic peptide semax shows neuroprotective and anti-inflammatory properties and is actively used in the treatment of ischemia.We have previously shown that semax reduces vascular injury and activates the mRNA synthesis of neurotrophins and their receptors under global cerebral ischemia in rats. Here we have analyzed the effects of semax and its C-terminal Pro-Gly-Pro tripeptide upon Vegfa mRNA expression in different rat brain regions after common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. It was shown that ischemia increases levels of Vegfa mRNA in the rat brain of animals (4 h after the occlusion--in the cerebellum, cerebral cortex and hippocampus, 8 h--in the cortex and hippocampus, and 24 h in the cortex). Semax treatment reduces Vegfa mRNA levels in the frontal cortex (4, 8 and 12 h after the occlusion) and hippocampus of ischemic rats (2 and 4 h). Effect of PGP on the Vegfa gene expression was almost negligible. Our results showed that semax prevents activating effect ofhypoxia on the Vegfa gene expression in early stages of global ischemia. Furthermore, increase in the level of mRNA Vegfa in the hippocampus (24 h after occlusion) perhaps reflects neuroprotective properties of this drug.

[Opposite Semax influence on conditioning and functional disturbances of avoidance responses in rats].

Semax effects on formation of active avoidance reaction in rats in different experimental models have been studied. It was shown that intraperitoneal Semax administration at a dose of 0.05 mg/kg accelerated acquisition of one-way active avoidance response when rats were trained to avoid electric foot-shock by jumping on the shelf. When rats were trained in shuttle-box the peptide increased the electroshock threshold value required to provocation of rat moving in experimental box and delayed acquisition of two-way active avoidance response. At the same time Semax stimulated avoidance response restoration in shuttle-box after functional disturbances induced by acute modification of cause-effect and spatial relationships in experimental environment. Data obtained support nootropic properties of Semax.

[Proteolysis of simple glyprolines by leucine aminopeptidase and enzymes from nasal slime, brain membranes, and rat blood].

Proteolysis of Pro-Gly-Pro-Leu, Pro-Gly-Pro-Gly and Pro-Gly-Pro were studied comparatively to Met-Glu-His-Phe-Pro-Gly-Pro (semax). It is shown that all three peptides are considerably more stable to proteolysis by N-leucine-aminopeptidase (EC 3.4.11.1, Sigma, type VI, 9.2 units/mg), and by enzymes of nasal slime, brain microsomal fractions, and rat blood. Metabolites of the proteolysis showed that semax derives His-Phe-Pro-Gly-Pro only, Pro-Gly-Pro-Leu forms Gly-Pro-Leu, Pro-Gly-Pro and Gly-Pro, Pro-Gly-Pro-Gly gives Pro-Gly-Pro and Gly-Pro, and Pro-Gly-Pro forms Gly-Pro.

[Cholesterol-lowering effect of the regulatory peptide Pro-Gly-Pro-Leu].

In the present paper anticoagulant-fibrinolytic effects of the peptide Pro-Gly-Pro-Leu in rats (370-500 g body weight) who consumed fatty foods with excess of saturated fatty acids (wheat flour and bread--35%, sugar--10%, margarine hydrogenated fats, mayonnaise, cheese--35% and offals--10%, cholesterol--1%, dry food--9%) has been established. The duration of the animals on the diet was 15 days. The experimental animals intranasally obtained peptide (200 microg/kg body weight per volume of 0.02 ml per 200 g body weight) 11 times (daily except weekends). Animals from the control group intranasally received instead of peptide its vehicle (0.85% solution of NaCl) at the same time and in the same amount. It has been shown that daily nasal administration of the regulatory tetrapeptide under fatty food intake for the entire period of the experiment has a positive effect on lipid metabolism. It warned the development of alimentary hypercholesterolemia, an increase in body weight, normalized disturbed lipid profile, blood cholesterol level. In addition, its administration also restored functional status of anticoagulation system and decreased elevated degree of blood coagulation to normal values. Possible mechanism of hypocholesterolemic activity of peptide can be explained by its ability to interact with receptors of blood or brain cells, and through a series of reactions mediated to reduce blood cholesterol levels. Thanks to the anti-platelet activity glyprolines effectively improves endothelial function and reduces the risk of blood clots in the blood vessels, providing improved rheological properties of blood and preventing the formation of atherosclerotic plaques in the arterial wall.

[Dynamic hierarchy of regulatory peptides. Structure of the induction relations of regulators as the target for therapeutic agents].

Based on the database information (literature period 1970-2010 gg.) on the effects of regulatory peptides (RP) and non-peptide neurotransmitters (dopamine, serotonin, norepi-nephrine, acetylcholine) it was analyzed of possible cascade processes of endogenous regulators. It was found that the entire continuum of RP and mediators is a chaotic soup of the ordered three-level compartments. Such a dynamic functional hierarchy of endogenous regulators allows to create start-up and corrective tasks for a variety of physiological functions. Some examples of static and dynamic patterns of induction processes of RP and mediators (that regulate the states of anxiety, depression, learning and memory, feeding behavior, reproductive processes, etc.) are considered.

[A complex of heparin with the peptide Arg-Pro-Gly-Pro and its anticoagulative, fibrinolytic, and hyperglycemia effects].

Heparin was bound to the arginine-containing peptide Arg-Pro-Gly-Pro with the molar ratio of heparin to the peptide 1:1. The complex compound showed antiplatelet, anticoagulative, and fibrin-depolymerization activities. In an in vivo study, in type 2 diabetes progression, a 5-fold intranasal administration of the compound restored both impaired insular and anticlotting functions in rats. Furthermore, blood fibrinolytic and anticoagulative activities increased.

[Proteolysis of semax analogues with different N-terminal amino acids by aminopeptidases].

Proteolysis of semax (Met-Glu-His-Phe-Pro-Gly-Pro, Sem) and its analogues ([Ala1]Sem, [Gly1]Sem, [Thr1]Sem, [Trp1]Sem) that are differ from semax in substitution of N-terminal Met residue were studied. It is shown that such replacement changes the rate of peptides degradation by N-aminopeptidases (EC 3.4.11.2, Sigma, Type VI, 9.2 units. Akt. / mg). [Ala1]Sem, [Gly1]Sem and [Thr1]Sem semax analogues proved to be more stable to proteolysis than semax (Sem), and their initial product of proteolysis is His-Phe-Pro-Gly-Pro (Sem-5). For triptophan analogue both Glu-His-Phe-Pro-Gly-Pro (Sem-6) and Sem-5 product are formed in similar quantities. It is found that all investigated analogues can be used as inhibitors in Sem proteolysis.

[Changes in expression of the genes for chemokines, cytokines, and their receptors in response to selank and its fragments].

A study of the immunomodulating effect of selank showed that the total peptide and its fragment significantly change the expression of the genes for chemokines, cytokines, and their receptors in mouse spleen 6 and 24 h after administration of a single dose. Changes in the mRNA level of the majority of the genes under study were similarly observed after the administration of Gly-Pro, which was earlier identified as a selank pharmacophor, a minimum fragment with anitiviral activity. Pharmacological preparations based on endogenous regulatory peptides are studied intensely because they are the most promising class of drugs and have almost no side effects. The class includes selank, which is a synthetic analog of taftsin. Selank exerts anxiolytic and nootropic effects and, on the other hand, has pronounced antiviral properties.

[The effect of semax and its C-end peptide PGP on expression of the neurotrophins and their receptors in the rat brain during incomplete global ischemia].

Neurotrophins regulate key function of nervous tissue cells. Analysis of neurotrophins mRNA expression is an appropriate tool to assess therapeutic efficiency of the anti-stroke drugs. We have analyzed the effect of synthetic peptide semax and its C-terminal Pro-Gly-Pro tripeptide upon mRNAs expression of neurotrophins Ngf, Bdrf, Nt-3 and their receptors TrkA, TrkB, TrkC, p75 in rat frontal lobes, hippocampus and cerebellum after bilateral common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. The mRNA expression of neurotrophins and their receptors was assessed by relative quantification using real-time RT-PCR. Our showed that ischemia causes a significant decrease in gene expression in the hippocampus. Semax and PGP affected the expression of neurotrophins and their receptors predominantly in the frontal cortex and hippocampus of the ischemized animals. In the frontal cortex, Semax treatment resulted in a decrease of mRNA level of receptors, while PGP treatment increased the level of these mRNA. Maximal neuroprotective effect of both peptides has been observed in the hippocampus 12 h after occlusion. A decrease of gene expression of neurotrophins and their receptors caused by the occlusion was overcome by Semax and PGP. These results clarify the semax mechanism of and present certain features of mRNA's expression of neurotrophins and their receptors in experimental conditions.

[Neurotensin-like oligopeptides as potential antipsychotics: effect on dopamine system].

According to published data, peptide neurotensin is considered as endogenous antipsychotic agent. A series of oligopeptides have been synthesized based on the proposed active center of neurotensin. These oligopeptides (called neurotensin-like peptides, NLPs) have been studied on behavioral models, in which the functional state of the dopamine system of animals was modified by apomorphine injections. The results of verticalization, stereotypy, and yawning tests revealed NLPs that behave as antagonists of dopamine receptors. Radioligand analysis showed that these peptides compete for specific binding to these receptors with sulpiride, which is a D2-type selective antagonist of dopamine receptors. The high degree of NLPs efficiency manifested in the behavioral tests and radioligand analysis suggests that the their antipsychotic action can be mediated by dopamine receptors.

[Protective antithrombotic effects of proline-containing peptides in the animal body subjected to stress].

We discovered that simple proline-containing peptides Gly-Pro, Pro-Gly, Pro-Gly-Pro, and semax had an antistress protective effect on the organism appearing as anticoagulation system activation. Repeated intranasal injection of each of these peptides to rats prior to acute immobilization stress prevented a hypercoagulation response to prolonged stress lasting 60 min. At the same time there was increase of antithrombotic, anticoagulant, and fibrin depolymerization activity and recovery of enzymatic fibrinolytic activity. Dipeptides were found to have the greatest antistress effect. Our results showed that semax had a protective effect against enhanced blood coagulability resulting from repeated immobilization stress.

[Fibrinolytic and hypoglycemic effects of the Pro-Gly-Pro-Leu peptide during development of insulin-dependent diabetes in rats].

Repeated (over 7 days) intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals at a dose of 1 mg/kg before injection of the diabetogenic metabolite alloxan provided effective protection of an organism against development of insulin-dependent diabetes mellitus and prevented development of hypercoagulating alterations in the system of hemostasis. An increasing in the anticoagulating and fibrinolytic activities in rat blood plasma was detected. The peptide under study also showed antidiabetogenic action: repeated intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals for 7 days inhibited development of diabetes symptoms in rats pretreated with alloxan.

[The synthesis of O-substituted 3-oximes of 6alpha-methyl-16alpha,17alpha-cyclohexanopregn-4-ene-3,20-dione tritium-labeled in 1 and 2 positions].

1,2-Tritium-labeled 3-(O-carboxypropyl)- and 3-(O-carbomethoxypropyl)-oximes of 6alpha-methyl-16alpha,17alpha-cyclohexanopregn-4-ene-3,20-diones were obtained by the homogeneous catalytic hydrogenation of 1,2-dehydroprecursors with gaseous tritium and the subsequent separation of the resulting mixtures by HPLC. The specific radioactivities of 50-55 Ci/mmol were prepared using tris-(triphenylphosphine)-rhodium chloride.

[Influence of Semax on the emotional state of white rats in the norm and against the background of cholecystokinin-tetrapeptide action].

The effects of the adrenocorticotropic hormone (ACTH(4-10)) analog, Semax (MEHFPGP), on the level of anxiety and depression in white rats have been studied in the normal state and against the background of cholecystokinin-tetrapeptide (CCK-4) action. Semax was injected intranasally in doses of 50 and 500 microg/kg 15 min before the testing. CCK-4 was administered intraperitoneally in a dose of 400 microg/kg 40 min before the testing. The level of anxiety was estimated in the elevated plus-maze test, and the degree of depression, in the forced swimming test. Semax administration did not influence the emotional state of animals in the normal state. The CCK-4 injection led to an increase in anxiety and depression in rats. Semax normalized the animal behavior disturbed by the CCK-4 administration, which attests to its anxiolytic and antidepressant effects at elevated levels of anxiety and depression.

[Nootropic and analgesic effects of Semax following different routes of administration].

Heptapeptide Semax (MEHFPGP) is the fragment of ACTH(4-10) analogue with prolonged neurotropic activity. The aim of the present work was to study the Semax effects on learning capability and pain sensitivity in white rats following intraperitoneal and intranasal administration in different doses. Semax nootropic effects were studied in the test of acquisition of passive avoidance task. Pain sensitivity was estimated in Randall-Selitto paw-withdrawal test. It was shown that Semax exerts nootropic and analgesic activities following intraperitoneal administration. Analysis of dependence of these effects on dose resulted in different dose-response curves. Following intranasal administration, Semax was more potent in learning improvement compared to intraperitoneal administration. The peptide failed to affect the animal pain sensitivity following intranasal administration as opposed to intraperitoneal administration. The data obtained suggest different mechanisms and brain structures involved in realization of the nootropic and analgesic effects of Semax.