[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.

[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.

[Study of long-lasting effects of acute prenatal stress induced forced swimming].

The aim of the present work was to assess long-lasting effects of acute prenatal stress in white rats. Forced swimming in cold water on the 7th or the 14th gestational day was used as a prenatal stressor. The prenatal stress led to low birthweight of offspring and their delayed growth rate during the second month of life. Prenatally stressed animals showed abnormalities in exploratory behavior and anxiety, increased emotionality and impaired learning capabilities at the age of 1-2 month. Consequently, acute stress on the 7th and at the 14th day of pregnancy induced long-lasting negative behavioral changes in offspring of stressed white rats.

[Melanocortin system].

Melanocortin system consists of native melanocortin peptides (ACTH, MSH and their fragments), melanocortin receptors (MC1R-MC5R) and their endogenous antagonists. Melanocortins have a wide spectrum of physiological activity. These peptides improve memory and attention, facilitate neuromuscular regeneration, exert neuroprotective action, affect the development of nervous system, modulate sexual behavior, have anti-inflammatory and antipyretic effects, interact with opioid system, affect the pain sensitivity and cardiovascular system, decrease food intake and body weight, influence on exocrine secretions.

[Studying the nootropic effects of betamecil].

Comparative study of the effects of methyluracil and betamecil showed that a fourfold oral administration of betamecil in a dose of 10 mg/kg leads to a considerable increase in the orientation-and-search reaction in the open field test. This drug effect is retained for at least one week. Betamecil in doses of 10 and 100 mg/kg does not virtually alter the rate of conditioning of the food-seeking reflex with respect to the place in the T-shaped maze test (as compared to the control animals. However, certain acceleration of the learning process is observed as compared to the animals treated with methyluracil. The chronic administration of betamecil (for 18 days) results in improved preservation and reproduction of the previously conditioned food-seeking habit. Neither piracetam nor methyluracil produced such effects. The results suggest that betamecil in indicated doses exhibits a nootropic activity.

[Effects of chronic Semax administration on exploratory activity and emotional reaction in white rats].

Effects of chronic intranasal administration of ACTH(4-10) analog Semax (MEHFPGP) on exploratory activity, anxiety level, and depression-like behaviour were studied in white rats. The peptide was injected daily in dose 0.05 mg/kg during 10 or 14 days. It was shown that chronic Semax administration at 1-2 weeks induced anxiolytic and antidepressant effects but did not influenced the exploratory activity in non-stressogenic environment. The Semax effects may be the results of activation of the brain serotoninergic system as well as increased BDNF expression in the rat hippocampus.

[Study of the relationship between analgesic activity and structure of synthetic melanocortin analogs].

Melanocortins, peptides of the family of adrenocorticotropic (ACTH) and melanocyte-stimulating (MSH) hormones, have a wide range of physiological activity. Heptapeptide semax (MEHFPGP) is an analog of the ACTH4-10 fragment. Previously, pronounced nootropic and neuroprotective activities were shown for this peptide; in addition, it decreases pain sensitivity in animals. In this work, the relationship between analgesic activity of the peptide and its structure was studied. The following analogs of the N-terminal ACTH fragments were used: rMEHFPGP, where r is glucuronic acid, KEHFPGP, GEHFPGP, EHFPGP, HFPGP, and ERP. The peptides were administered intraperitoneally at doses of 0.015, 0.05 and 0.5 mg/kg. Rat pain sensitivity was assessed using the paw-withdrawal test. Truncations of the N-terminal residues eliminated the analgesic activity. The peptide analgesic effect was observed after the replacement of the N-terminal methionine with lysine or after the attachment of glucuronic acid to the methionine, while the peptide with glycine instead of the methionine had no effect on pain sensitivity. Hence, the amino acid at position 1 of semax analogs plays a key role in mediating the analgesic effects of the peptides.

[Kinetics of Semax penetration into the brain and blood of rats after its intranasal administration].

The radioactive peptide analogue Semax corresponding to the ACTH(4-10) sequence (Met-Glu-His-Phe-Pro-Gly-Pro) with a molar radioactivity of 56 Ci/mmol labeled with tritium at the C-terminal Pro was prepared. The labeled peptide was used for studying the kinetics of Semax penetration into rat brain and blood after its intranasal administration (50 microg/kg, 20 microl of solution) to nonbred white rats of body mass 200-250 g. It was demonstrated that 0.093% of the total introduced radioactivity per gram can be found in the rat brain 2 min after the administration, 80% of this radioactivity belonged to Semax, and the rest, to its metabolites. The peptide undergoes rapid enzymatic degradation, with the tripeptide Pro-Gly-Pro prevailing in biological samples relative to the total content of Semax and its metabolites.

[Effect of modification of the N-terminal region of molecule on the expression of neotropic effect of semax analogues].

A comparative study of neotropic activity of semax (MEHFPGP), an analogue of the ACTH(4-10), and some of its derivatives in which the N-terminal methionine was modified or substituted with other amino acid residues was performed. The effect of these peptides on learning of albino rats in tests with positive (alimentary) and negative (pain) reinforcement was studied. In the case of modification of methionine by attachment of the gluconic-acid residue or substitution of methionine with lysine, the neotropic effect of the peptide was retained. The substitution of methionine with tryptophan or serine resulted in a decrease in the neotropic activity. The substitution of methionine with glycine, threonine, or alanine caused a complete loss of the neotropic activity of the peptide. Therefore, the amino acid residue located at position 1 of the heptapeptide analogue semax, plays a key role in retaining the neotropic effects of the peptide and determines the degree of their expression.

[Long-lasting behavioral effects of chronic neonatal treatment with ACTH (4-10) analogue semax in white rat pups].

It is well known that ACTH/MSH-like peptides (melanocortins) have neurotrophic and neuroprotective effects on the central and peripheral nervous systems in the early postnatal life. The aim of present work was to study consequences of the ACTH (4-10) analogue Semax influence on the developing brain. The work was carried out in white rat pups. The peptide (0.05 mg/kg, i/p) was injected daily on the 8th-21st postnatal days. Delayed long-lasting effects of such treatment on animal behavior were revealed. At the age of four to eight weeks, Semax-treated rats displayed elevated exploratory activity, decreased anxiety level and improved passive avoidance conditioning. The results suggest that neonatal Semax administration modulates the development of the central nervous system.

[Dependence of long-lasting effects of the ACTH(4-10) analogue semax on the time of its neonatal administration].

Long-lasting behavioural effects of chronic administration of synthetic ACT(4-10) analogue Semax (MEHFPGP) during early neonatal life were studied. The peptide was injected daily intraperitoneally in dose 0.05 mg/kg during the first, second or second-third weeks of postnatal development. It was shown that the peptide injections during the first week lead to a decrease and during second or second-third weeks--to an increase of exploratory activity in 4-8-week aged rats. Furthermore, the peptide adminictration at all times diminished anxiety and improved learning ability of adult rats. The data obtained show that Semax neonatal administration during the first three weeks of life modulates development of brain structures involved in regulation of exploration, anxiety and learning.

[An experimental substantiation for using the "Semax" neuroprotector in the treatment of optic-nerve diseases]. / Eksperimental'noe obosnovanie ispol'zovaniia neiroprotektora semaksa v lechenii zabolevanii zritel'nogo nerva.

In order to substantiate the feasibility of using the "Semax" neuroprotector in the treatment of optic-nerve diseases its pharmacokinetics in the intranasal administration was studied in experiments with rats; besides, the physical-and-chemical properties of "Semax" were investigated to define the preparation's stability and mobility in the electric field. A series of experiments, involving a tritium-marked "Semax", showed that the peptide actively penetrates into the brain and eyes of experimental animals after its intranasal administration. It was established, within a study aimed at determining the electrophoretic activity and stability of "Semax" in the electric field, that the preparation does not disintegrate in the electric field, it posses the electrophoretic mobility and moves, in the electric field, from plus to minus; therefore, the "Semax" solution must be fed from anode while making the electrophoresis procedure.

[Highly stable regulatory oligopeptides: experience and applications]. / Vysokostabil'nye reguliatornye oligopeptidy: opyt i perspektivy primeneniia.

The most stable regulatory peptides (RP) including the new family of RP (glyprolines) and derivatives of hybrid peptide MEHFPGP are characterized. High ability of glyprolines to penetrate into the blood-stream through the gastrointestinal tract is demonstrated. Antiulcer, antithrombotic and antidiabetic activities of glyprolines were discovered in experiments on white rats. The activity of oligopeptides PGP, PG and GP is compared. Mechanisms of glycoprolines activities and feasibility of their administration with connective tissue food proteins are discussed. Thus, glyprolines are perspective drugs for treatment of gastric ulcer, correction of hemostasis and thrombosis suppression prepared for preclinical trial.

[Neuroprotective effects of semax in MPTP-induced disturbances of brain dopamine system]. / Neiroprotektornye éffekty semaksa na fone MFTP-vyzvannykh narushenii dofaminergicheskoi sistemy mozga.

Effects of an ACTH (4-10) analogue Semax (MEHFPGP) on behaviour of white rats with MPTP-induced disturbances of brain DA-system have been studied. It was shown that MPTP administration (25 mg/kg) reduced motor activity and auhmented the anxiety level in rats. Semax administration (daily intranasal 0.2 mg/kg) attenuated behaviour disturbances induced by neurotoxin. The observed protective action of Semax in rats with MFTP-induced DA system disturbances may be due to both its modulating influence on the brain DA system and peptide neuroprotective effects.

[Dependence of neuropeptide physiological effects on a route of administration]. / Zavisimost' fiziologicheskikh éffectov riada neiropeptidov ot puti vvedeniia.

Following intranasal administration, the peptides' effects could remain either the same as following an invasive administration (ACTH4-10) which is important for clinical application, or enhanced and prolonged (demorphin and argynilvasopressin analogue), or modified (beta-casomorphin-7). Techniques of improvement of the peptides' regulatory efficacy through protection against the protease action, are discussed. Peptide protection by introducing D-aminoacid's isomers into its molecule or addition of proline-rich sequences were compared. The latter technique seems to be more effective.

[Effect of low-molecular peptides on the transformation of fibrinogen into fibrin]. / Vliianie nizkomolekuliarnykh peptidov na protsess perekhod fibrinogenav fibrin.

The influence of synthetic peptides on fibrinogen transformation to fibrin under the action of thrombin and fibrin-monomer polymerization was investigated. Peptides Gly-Pro-Arg-Pro; Gly-Pro-Arg-Pro-Lys; Gly-Pro-Arg-Pro-Lys-Boc; Gly-Pro-Arg-Pro-Arg are specific inhibitors of fibrin formation. These peptides interfere with the hydrolysing effect of thrombin due to binding to the central domain of fibrinogen. The interaction of peptides with peripheral D-domains of fibrin-monomer may account for polymerization inhibition. The latter peptide has the largest anticoagulation activity. It is likely that arginine in the fifth position stabilizes the structure of the peptides, with the additional epsilon NH2-group activating its interaction with protein.