Selank

Selank, a Peptide Analog of Tuftsin, Attenuates Aversive Signs of Morphine Withdrawal in Rats.

M A Konstantinopolsky, I V Chernyakova, L G Kolik

Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (р<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.

Sedative-Hypnotic Agents That Impact Gamma-Aminobutyric Acid Receptors: Focus on Flunitrazepam, Gamma-Hydroxybutyric Acid, Phenibut, and Selank.

Cassandra R Doyno, C Michael White

There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues.

GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells.

Elena Filatova, Anastasiya Kasian, Timur Kolomin +8 more

Clinical studies have shown that Selank had an anxiolytic effect comparable to that of classical benzodiazepine drugs, which can enhance the inhibitory effect of GABA by allosteric modulation of GABAA receptors. These data suggest that the molecular mechanism of the effect of Selank may also be related to its ability to affect the performance of the GABAergic system. To test this hypothesis, we studied the changes in expression of 84 genes involved in the functioning of the GABAergic system and in the processes of neurotransmission in the culture of neuroblastoma IMR-32 cells using qPCR method. As test substances, in addition to Selank, we selected the major GABAA receptor ligand, GABA, the atypical antipsychotic, olanzapine, and combinations of these compounds (Selank and GABA; Selank and olanzapine). We found no changes in the mRNA levels of the genes studied under the effect of Selank. The combined effect of GABA and Selank led to nearly complete suppression of changes in expression of genes in which mRNA levels changed under the effect of GABA. When Selank was used in conjunction with olanzapine, the expression alterations of more genes were observed compared with olanzapine alone. The data obtained indicate that Selank has no direct effect on the mRNA levels of the GABAergic system genes in neuroblastoma IMR-32 cells. At the same time, our results partially confirm the hypothesis that the peptide may affect the interaction of GABA with GABAA receptors. Our data also suggest that Selank may enhance the effect of olanzapine on the expression of the genes studied.

Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content in the Hippocampus and Prefrontal Cortex in Rats.

L G Kolik, A V Nadorova, T A Antipova +3 more

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.

Peptide-based Anxiolytics: The Molecular Aspects of Heptapeptide Selank Biological Activity.

Tatiana V Vyunova, Lioudmila Andreeva, Konstantin Shevchenko +1 more

Anxiety and mood disorders are the most abundant mental health problems worldwide. The commonly used in clinical practice anxiolytics are focused on pharmacological modulation of brain GABA receptor system activity. As a rule, their use presents a wide spectrum of clinical issues such as dependence, memory impairment and etc. There is an increasing appreciation of the role of neuropeptides and bioactive lipids in the pathophysiology of mood and anxiety disorders as "mild" agents. Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) exhibits prolonged anti-anxiety and nootropic effects.

[COMPARISON OF PHARMACOLOGICAL EFFECTS OF HEPTAPEPTIDE SELANK AFTER INTRANASAL AND INTRAPERITONEAL ADMINISTRATION TO BALB/c AND C57BL/6 MICE.].

E V Vasil'eva, E A Kondrakhin, R M Salimov +1 more

Pharmacological effects of intraperitoneal (i.p.) and intranasal (i.n.) administration of heptapeptide selank (300 μg/kg/day for 5 days), known to possess anxiolytic and nootropic properties, were compared by studying the elevated-plus-maze behavior of inbred BALB/c and C57BL/6 mice and measuring the binding of markers to NMDA and GABA receptors of brain. The anxiolytic and nootropic efficiency of selank administered via both routes was observed only in BALB/c mice, which were characterized by initially reduced exploratory activity and higher levels of anxiety as compared to C57BL/6 mice. In BALB/c mice, i.p. selank increased the number of [G-(3)H]SR 95531 binding sites with GABA-receptors in the frontal cortex by 38%, without change in binding to NMDA receptors in the hippocampus. On the contrary, i.n. selank led to an increase in the density of [G-(3)H]MK-801 binding sites by 23% with no effect on GABA receptors. It is suggested that the differences in pharmacological spectra observed for the two routes of selank administration are determined by specific features of drug pharmacokinetics and biotransformation as well as by the dynamics of formation of the anxiolytic and nootropic effects of selank.

Effect of Selank on Spontaneous Synaptic Activity of Rat Hippocampal CA1 Neurons.

I S Povarov, R V Kondratenko, V I Derevyagin +2 more

Application of anxiolytic drug Selank to hippocampal slices increased the amplitude and discharge rate of spontaneous inhibitory postsynaptic currents in rat hippocampal pyramidal CA1 neurons. In some neurons, Selank-induced up-regulation of spontaneous inhibitory postsynaptic currents was preceded by a transient decrease in this activity. In the examined concentration range (1-8 μM), Selank demonstrated no significant dose-dependence.

Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats.

Anastasiya Kasian, Timur Kolomin, Lyudmila Andreeva +4 more

It was shown that the anxiolytic effect of Selank is comparable to that of classical benzodiazepine drugs and that the basis of their mechanism of action may be similar. These data suggest that the presence of Selank may change the action of classical benzodiazepine drugs. To test this hypothesis, we evaluated the anxiolytic activity of Selank and diazepam in rats both under conditions of unpredictable chronic mild stress and in its absence, after the individual and combined administration of these compounds using the elevated plus maze test. We found that, even in the absence of chronic stress, the administration of a course of test substances changed anxiety indicators toward their deterioration, but the changes after the administration of a course of Selank were less pronounced. In conditions of chronic stress, anxiety indicator values after the simultaneous use of diazepam and Selank did not differ from the respective values observed before chronic stress exposure. The data obtained indicate that the individual administration of Selank was the most effective in reducing elevated levels of anxiety, induced by the administration of a course of test substances, whereas the combination of diazepam with Selank was the most effective in reducing anxiety in unpredictable chronic mild stress conditions.

Selank Inhibits Ethanol-Induced Hyperlocomotion and Manifestation of Behavioral Sensitization in DBA/2 Mice.

L G Kolik, A V Nadorova, S B Seredenin

The effect of non-benzodiazepine anxiolytics on the ethanol-induced hyperlocomotion and behavioral sensitization was assessed in male DBA/2 mice. Selank that enhances activity of the endogenous opioid system (0.3 mg/kg, intraperitoneally), similar to the nonselective opiate receptor blocker naloxone (1.0 mg/kg, intraperitoneally), prevented the development of ethanol-induced (2.0 g/kg intraperitoneally) hyperlocomotion, in contrast to σ1-receptors agonist Afobazole (1.0 mg/kg, intraperitoneally) that did not inhibit ethanol-induced behavioral stimulation. Single dose of Selank significantly blocked manifestation of motor sensitization without affecting its formation. These findings suggest that Selank can modulate the motivational effects of ethanol.

[Optimization of the treatment of anxiety disorders with selank].

V E Medvedev, O N Tereshchenko, N V Kost +5 more

To compare the efficacy and tolerability of monotherapy with phenazepam to complex treatment with the peptide preparation selank and phenazepam in patients with anxiety disorders.

Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation.

L G Kolik, A V Nadorova, M M Kozlovskaya

We studied the effects of selank on the development of symptoms of acute 48-h alcohol withdrawal in outbred rats drinking 10 % ethanol as the only source of fluid for 24 weeks. In alcohol-preferring animals (mean daily ethanol intake >5.0 g/kg) allowed free choice between 10 % ethanol and water, single intraperitoneal injection of selank in a dose of 0.3 mg/kg eliminated anxiety induced by ethanol withdrawal in tests elevated plus maze and social interaction tests and prevented the formation of mechanical allodynia without affecting ethanol consumption. The fi ndings suggest that selank is effective in eliminating of alcohol withdrawal symptoms in rats.

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

V E Medvedev, O N Tereshchenko, A Iu Israelian +4 more

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.

[Protective effect of selank on the model of mnestic function violation induced by pharmacological blockade of protein synthesis].

I I Kozlovskiĭ, F Iu Belozertsev, L A Andreeva +1 more

We have studied the ability of peptide anxiolytic selank (Thr-Lyz-Pro-Arg-Pro-Gly-Pro) to compensate for mnestic dysfunction caused by the administration of actinomycin D, which inhibits protein synthesis by blocking DNA-dependent RNA polymerase. The experiments were performed on white rats with acquired adaptive ability of spatial visual orientation in a 16-door labyrinth. The learning was based on the avoidance of electric skin irritation at alternating sites of escape reaction (site reflex). Selank (0.5 mg/kg, i.p.) prevented or compensated for actinomycin D (250 mg/kg, i.p.) induced violation of the process of acquisition, improvement, and consolidation of memory trace during the development of a complex site reflex. The drug administration also reduced the time required for acquisition of the adaptive ability of spatial visual orientation in the labyrinth and restored the actinomycin D violated process of re-learning upon a change in the alternation of escape sites under free-choice conditions.

[The role of opioid system in peculiarities of anti-anxiety effect of peptide anxiolytic selank].

I I Kozlovskiĭ, L A Andreeva, M M Kozlovskaia +2 more

Peculiarities of the anxiolytic effects of selank (heptapeptide analog of taftsin) under reduced activity of opioid system upon acute administration of naloxone have been studied in BALB/C and C57BL/6 inbred mice with high and low levels of anxiety, with passive and active emotional stress reaction phenotypes in the open field (OF) test. Selank (0.25 mg/kg, i.p.) per se exhibited anxiolytic effect in BALB/C mice by increasing the general locomotor activity, with no effects on the behavior of C57BL/6 mice in the OF test. Naloxone (1.0 mg/kg, i.p.) per se evoked swift runaway in OF peripheral areas in BALB/C mice while "freezing" the reaction in C57BL/6 mice with active response to stress under the same conditions. Pretreatment with naloxone attenuated the sensitivity to selank in BALB/C mice whereas the response to anxiolytic effects of peptide was increased in C57BL/6 mice. The data obtained reveal a new target for selank in CNS and indicate significance of the activity of enkephalin-opioid system in individual sensitivity to selank.

[Peptidergic modulation of the hippocampus synaptic activity].

V G Skrebitskiĭ, R V Kondratenko, I S Povarov +1 more

Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent.

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

T A Kolomin, M I Shadrina, P A Slominskiĭ +2 more

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.

[Effects of heptapeptide selank on the content of monoamines and their metabolites in the brain of BALB/C and C57Bl/6 mice: a comparative study].

V B Narkevich, V S Kudrin, P M Klodt +4 more

The effect of heptapeptide selank on the content of neurotransmitter monoamines and its metabolites in the brain structures of BALB/C and C57Bl/6 line mice under conditions of the open-field test were studied. Significant interstrain differences in the content of norepinephrine (NE), dopamine (DA), serotonin (5-HT) as well as in the levels of their metabolites in hippocampus, hypothalamus, striatum and frontal cortex of C57Bl/6 and BALB/C mice were demonstrated. In particular, the content of 5-HT and its metabolite 5-oxyindolacetic acid (5-HIAA) in hippocampus of BALB/C mice (with passive stress response) was higher than in the same structure of C57Bl/6 (stress-susceptible) animals. The injection of selank (0.3 mg/kg) led to an increase in the NE level in the hypothalamus of both mice strains. At the same time, selank produced opposite effects on the content of DA metabolites: the concentrations of dioxyphenylacetic (DOPAC) and homovanillic (HVA) acids were found to increase in frontal cortex and hippocampus of C57Bl/6 mice, while the same parameters in BALB/C mice were demonstrated to decrease. Selank induced a decrease in 5-HT and 5-HIAA levels in the hippocampus of BALB/C mice, but did not affect these parameters in C57Bl/6 animals. The obtained results are indicative of selectivity of the anxiolytic effects of selank.

[Compensatory and antiamnestic effects of heptapeptide Selank in monkeys].

The work presents results of study of role of heptapeptide Selank--an anxiolytic from group of biologically active peptides--in compensation of disturbed psychic and homeostatic functions in monkeys. New data have been obtained which indicate that an intranasal administration of Selank produces long-term changes of the monkeys' behavior disturbed during neurosis: elimination of fear and aggression and an increase of orientational-explorative activity as well as facilitation of handling reactions and communicational relations. It has been established that on the background of the Selank there occurs a long compensation of disturbed psychic functions (processes of memory) and of homeostatic parameters. It has been shown that unlike the earlier studied neurohormones (thyroliberin and ACTH4-10), the antistressor Selank effects do not depend on the type of neurotic disturbances and have long-term compensatory character. Comparison of the data obtained on monkeys with results of similar studies on the more low-organized mammals (rodents) allow suggesting that the new peptide preparation Selank is a promising agent for correction of various psychoemotional disturbances (alarm- and depression-like disorders).

[Effects of heptapeptide selank on genetically-based and situation-provoked symptoms of depression in behavior in WAG/Rij and Wistar rats, and in BALB/c mice].

K Iu Sarkisova, I I Kozlovskiĭ, M M Kozlovskaia

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

[Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].

A A Zozulia, G G Neznamov, T S Siuniakov +11 more

Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.

[Compensatory effect of selank on the mnestic functions disturbed by neurotoxic damage of the noradrenergic system of the rat brain].

I I Kozlovskiĭ, Iu F Belozertsev, T P Semenova +2 more

It has been shown that the peptide anxiolytic drug Selank recovers learning and memory impaired by damage of the noradrenergic (NA) brain system in Wistar rats after injection of the NA-synthesis inhibitor disulfiram, administration of neurotoxic compound 6-OHDA, or a combined induction of hypoxic hypoxia and hypercapnia. The main component of the Selank action is the stimulation of the search reflex aimed to distinguish an adequate adaptive response in the first trials of the learning session. The enhancement of memory consolidation and retrieval shows evidence for stimulation of the brain motivation mechanisms impaired by the NA system damage.

Selank and its metabolites maintain homeostasis in the gastric mucosa.

T S Pavlov, G E Samonina, Z V Bakaeva +2 more

Antiulcer properties of a synthetic anxiolytic Selank and in vivo formed metabolites of this compound were studied on 3 experimental models of ulceration. The test peptides decreased the area of experimental gastric ulcers.

Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.

V K Meshavkin, N V Kost, O Yu Sokolov +3 more

Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.

Influence of long-term treatment with tuftsin analogue TP-7 on the anxiety-phobic states and body weight.

Róza Czabak-Garbacz, Beata Cygan, Lukasz Wolański +1 more

TP-7 is a synthetic analogue of tuftsin. It has a structure of tuftsin, to which three natural L-amino-acids Pro-Gly-Pro are attached. This heptapeptide improves learning and memorization and causes antidepressant and anxiolytic effect. It is possible to use TP-7 in the future to optimize cognitive functions and as a potential new anxioselective, fast-acting and easy-dosed drug. Therefore, it was purposeful to study such properties of the heptapeptide as its influence on anxiety-fear and body weight under a long-term treatment regimen. The experiment was performed on 24 preselected Wistar rats with the use of Rodina's method. There were three experimental groups of animals with high initial emotional reactivity: passive control group (P), active control group (A, receiving distilled water) and group treated with TP-7 at the dose of 0.3 mg/kg (T). The rats of A and T groups received intraperitoneal injections every day. The experiments were conducted 15 min after the administration of the drug, one and two days after initial testing day, then 1, 2, 3 and 4 weeks after that. The heptapeptide reduced the anxiety-phobic states significantly starting from the second day of drug application. The observed effects persisted throughout four weeks of the experiment, which confirmed effective long-term anxiolytic properties of the heptapeptide. TP-7 did not cause any changes in the body mass by itself.

[Evenly tritium-labeled peptides and their in vivo and in vitro biodegradation].

Iu A Zolotarev, A K Dadaian, O V Dolotov +19 more

Biologically active peptides evenly labeled with tritium were used for studying the in vitro and in vivo biodegradation of the peptides. Tritium-labeled peptides with a specific radioactivity of 50-150 Ci/mmol were obtained by high temperature solid phase catalytic isotope exchange (HSCIE) with spillover tritium. The distribution of the isotope label among all amino acid residues of these peptides allows the simultaneous determination of practically all possible products of their enzymatic hydrolysis. The developed analytical method includes extraction of tritium-labeled peptides from organism tissues and chromatographic isolation of individual labeled peptides from the mixture of degradation products. The concentrations of a peptide under study and the products of its biodegradation were calculated from the results of liquid scintillation counting. This approach was used for studying the pathways of biodegradation of the heptapeptide TKPRPGP (Selank) and the tripeptide PGP in blood plasma. The pharmacokinetics of Selank, an anxiolytic peptide, was also studied in brain tissues using the intranasal in vivo administration of this peptide. The concentrations of labeled peptides were determined, and the pentapeptide TKPRP, tripeptide TKP, and dipeptides RP and GP were shown to be the major products of Selank biodegradation. The study of the biodegradation of the heptapeptide MEHFPGP (Semax) in the presence of nerve cells showed that the major products of its biodegradation are the pentapeptide HFPGP and tripeptide PGP. The enkephalinase activity of blood plasma was studied with the use of evenly tritium-labeled [Leu]enkephalin. A high inhibitory effect of Semax on blood plasma enkephalinases was shown to arise from its action on aminopeptidases. The method, based on the use of evenly tritium-labeled peptides, allows the determination of peptide concentrations and the activity of enzymes involved in their degradation on a tg scale of biological samples both in vitro and in vivo.

[Effects of the new peptide anxiolytic drug selank on the cardiovascular system functioning and respiration in cats].

T S Gan'shina, I I Kozlovskiĭ

The effects of the new heptapeptide anxiolytic drug selank (300 mg/kg, i.v.) on the arterial pressure (AP), cerebral blood flow, heart rhythm, respiration, and the AP depression induced by acetylcholine injections was recorded in narcotized male cats. Selank produced a 32 +/- 4.3% decrease in the AP for the first 1-3 min after injection. The drug also induced a 24 +/- 2.8% increase in the cerebral blood flow for the first 5 - 10 min upon injection and then the blood flow was gradually restored on the initial level. The heart rate and the respiratory rate were not affected by the drug injections. Nor did selank influence the AP depression in response to the acetylcholine introduction.

[Effect of new synthetic anxiolytic selank on gastric wall blood flow and mesenteryc lymphatic vessels contractility in anesthetized rats].

T S Pavlov, L Ts Sanzhieva, G E Samonina +2 more

The influence of a new heptapeptide Selank on microcirculation in anesthetized white rats was investigated. Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is a new synthetic anxiolytic which exerts obvious antiulcerogenic action and promotes healing of experimental ulcers. Action of the peptide on gastric blood flow in the stomach by using the method ofhydrogenic clearance and Selank action on mesenteric lymphatic contractility by microscopical observation in situ, were studied. Selank fail to influence basal gastric blood flow but it can normalize blood flow reduced by indomethacin. The study of dose-depended of Selank effect on lymphatic vessels contractility showed that its low concentration (10(-12)--10(-14) M) enhanced amplitude and increase frequency of lymphatic vessel contractions which indicates an enhancement of lymphatic flow. The high doses of peptide (10(-6)--10(-10) M) also augmented the contraction amplitude but decreased its frequency. The maintenance of adequate blood flow and lymphatic vessel contractility can be one of the mechanisms of the Selank antiulcerogenic properties.

A new property of the synthetic anxiolytic Selank and its derivatives.

T S Pavlov, G E Samonina, L A Andreeva +2 more

Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress.

M M Kozlovskaya, I I Kozlovskii, E A Val'dman +1 more

White laboratory male rats, inbred male C57BL/6 and Balb/c mice, and male Wistar rats, all previously divided on the basis of the type of emotional reactivity, were used to compare the effects of ten peptide compounds of the tuftsin family and Selank on the behavioral manifestations of emotional stress created by a conflict situation. Peptides were shown to have positive emotional effects and antistress actions. Individual physiologically significant effects were seen, due to the molecular structures of the study peptides and/or their degradation fragments. The results demonstrate the potential for the synthesis of peptide compounds with predictable directions of pharmacological actions and safe for wide use.