[Research of interactions in the dopamine-serotonin-somatostatin system promises new outlook in fundamental and practical respects].

Dopamine and serotonin are the two important key neurotransmitters, which participate in the formation and regulation of various physiological parameters in the normal and pathological states. It is very interesting and important in both fundamental and practical respect to analyze interactions of dopamine and serotonin with somatostatin--a peptide hormone suppressing the secretion of many other regulatory peptides and various bioactive substances. In the present work, a huge amount of experimental data on the interactions of dopamine and serotonin with somatostatin was collected and analyzed. Literature sources mainly cover the period of 1970 - 2006. Compilation of an information database on dopamine/serotonin--somatostatin interactions has been the next stage. Analysis of the effects of dopamine and somatostatin revealed unilateral influence of these endogenous regulators and also of the induced and/or inhibited peptides on the level of depression, stress, food intake, angiogenesis and cancerogenesis, thus making it possible to increase and prolong their effects via cascade mechanisms. Potentially possible combinations of somatostatin and dopamine analogs, and chimeric somatostatin/dopamine molecules are proposed for the treatment and correction of different pathological states, including acromegaly, prolactinemia, and hyperinsulinism.

[Antidiabetogenic action of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides after their intranasal chronic administration to animals].

It was shown that chronic (over 7 days) intranasal injection of the Pro-Gly-Arg tripeptide to rats in the dose 1 mg/kg before the injection of a diabetogenic dose of alloxan, promotes effective defense against development of insulin dependent diabetes mellitus. At the same time, the tetra-peptide Pro-Gly-Pro-Arg did not show a hypoglycemic affect during diabetes mellitus provocation. Administration of Pro-Gly-Arg and Pro-Gly-Pro-Arg peptides also activates anticoagulation potential.

[A comparative analysis of distribution of glyprolines administered by various routes].

The distribution of the glyprolines Pro-Gly-Pro and Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selanc) was analyzed and compared in tissues of rat organs after different ways of their administration using the peptides uniformly labeled with tritium. Comparative data on changes in concentrations of the peptides in the rat organs after their intraperitoneal, intranasal, intragastric, and intravenous administration are given. The intranasal administration of both peptides was shown to be optimal for the delivery of glyproline molecules in the CNS. A high affinity of the studied glyprolines for gastric tissues was found for all the ways of their administration. We suggest that a high efficiency of action of glyprolines on homeostasis of the gastric mucous tunic was partially provided by accumulation of these peptides (to high concentrations) in gastric tissues.

[The interaction of serotonin and dopamine systems with the systems of the regulatory peptides oxytocin, vasopressin, and prolactin under normal conditions and during pregnancy].

The authors studied a vast volume of unsystematized literature data (between 1970 and 2006) on the interaction of the neurotransmitters serotonin and dopamine with the hormonal peptide regulators prolactin, oxytocin, and vasopressin. Analysis of the results of studies made it possible to create a data base and analyze complex induction interactions between serotonin and dopamine and the three regulatory peptides under various physiological conditions: non-pregnancy, early and late stages of pregnancy, lactation, and maternal behavior. The roles of serotonin and dopamine in the formation of reproductive and maternal behavior were determined. The article presents possibilities for research into positive intervention into the hormonal status of a pregnant woman via a range of psychotropic drugs.

[Search for evolutionary ancient, relict regulatory peptides].

Among numerous regulatory peptide (RP) it is possible to presumably indicate the relict, evolutionary ancient RP. They combine three features: formation from non-specialized proteins-precursors, a comparatively high resistance to action of proteases in the organism media, and maximal simplicity of their structure. The examples of them are glyprolines--a recently identified RP family, as well as tuftsin. Several other praline-containing RP in terminal sites also seem to belong to the evolutionary ancient RP. The proposed approach to studies on the RP evolution is additional to those used traditionally in this problem.

[Synactones--functionally conjugated complexes of endogenous regulators].

All physiological processes are regulated by complexes of various endogenous compounds (EC), acting in definite sequences and combinations. The effort to model the regulation by introducing separate ECs provides only partial information. This circumstance also limits the therapeutic efficiency of separate ECs and their stabilized derivatives. Therefore, it is obviously necessary to extensively investigate various EC complexes, for which a conventional name of "synactones" is proposed. It is expedient to use this name only for conjugated EC (or their stabilized derivatives) rather than to various drug combinations with compositions and structures far from those of the endogenous regulators of animal organism. Examples of the most promising synactones (in the form of mixtures of ECs or covalently associated ECs) are presented. Specific methodological difficulties of such investigations, as well as the problems related to various ways of administration and blood-brain barrier penetration are considered.

[Interactions between dopamine, serotonin and other internal reinforcement factors].

The big volume of odd literature data (period 1960-2005) was investigated for analysis and estimation of interactions between dopamine (DA), serotonin (5-HT), reward factors and basic members of regulatory peptide (RP) families. Database, which includes information about physiological effect directions, doses and administration types of RP and biological active compounds, organism types, organ-tissues systems and receptor mechanisms was created. The complex cascade interactions between DA, 5-HT, reward factors and RP were investigated and systemized. Based on analysis of correlated functiong of DA and 5-HT-systems, the opponent-reciprocal interactions were established and their integrative characteristics were estimated.

[Development and application of an expert system for analysis of the functional continuum of regulatory peptides].

An expert computer system was developed to analyze the effects of regulatory peptides (RPs) and some other biologically active compounds. The database includes information on their structures and physiological and inductive effects taking in account the method of administration, doses, and types of organisms. The developed method of vector representation of RP effects and the software modules provide for the estimation of the role of single RPs and their combinations in the regulatory system of organism. The expert system was used for solving the following tasks: (1) an analysis of the structural and functional organization of the RP continuum and a search for effective RP combinations regulating the levels of anxiety, depression, cognitive processes, etc; (2) design of a network of complicated cross inductive connections of major members of RP families; and (3) an analysis of the peculiar features of functioning of numerous internal reward factors. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2006, vol. 32, no. 3; see also http://www.maik.ru.

[Reculatory fragments of collagen in gastric mucosa homeostasis].

The new glyproline family was distinguished from the regulatory peptides recently. It includes the simplest proline- and glycine-containing peptides: PG, GP, PGP, and respective peptides with hydroxylated proline residues. Glyproline's bioactivity covers many important systems of the body including suppression of some reaction in the blood coagulation and platelet aggregation and gastric mucosal maintenance. It was shown that PGP, PG and GP have a wide spectrum of antiulcer activity with respect to gastric mucosal damages of various aetiology. GHyp and HypGP show also antiulcer action. In vivo glyprolines being fragments of collagen may be generated during synthesis and catabolism of collagen. It is well known that approximately 10-60% of newly synthesized collagen degrade intracellularly with succeeding secretion of small peptides composed of less than 5 aminoacid residues out of cells. Different simplest proline and hydroxyproline fragments of glyprolines are revealed in various type of collagen: GP, GHyp, PG, PPG, PGP, PHypG., GPHyp, GPP, GPG, GHypP, HypGP. It is possible that these fragments may be also secreted out of cells during the stage of degradation of newly synthesized collagen. We showed that the intragastric (per oral) introduction of hydrolyzed gelatin, having 20 small peptide fragments, including PGP and HypGP, also increase gastric stability showing protective and therapeutic antiulcer effect. The corresponding receptors for glyprolines are not completely identified yet but it may be supposed that PGP, GP and other glyprolines interact with the same receptors with which the III type collagen is binding with platelet's receptors. It is supposed that octapeptide sequence KPGGluPGPK of collagen is rather important for binding with receptor. When this sequence in the structure of collagen's molecule binds with the receptor, platelet aggregation is induced. Free octapeptide blocks the receptor and inhibits platelet aggregations. Qualitatve characteristics of parameters of inhibition with intact octapeptide and glyproline, as well as the receptor's structure--that's our concern for the nearest future.

[Reversible inhibitory action of adenosine diphosphate ribose on isolated rat heart and rat heart in vivo].

Cardiotropic effects of endogenous regulator of intracellular ionic balance adenosine diphosphate ribose (ADP-ribose) was studied on isolated rat heart using standard retrograde perfusion and on rat heart in vivo by means of implanted arterial catheters. Parameters registered were heart rate, pressure developed in left ventricle of isolated heart and blood pressure of rats in vivo. It was shown that ADP-ribose exerted cardiotropic action on isolated rat heart and that its effects did not depend on effects of its metabolite AMP. In concentrations 10-70 microM ADP-ribose caused negative dose dependent chronotropic effect. Amplitude of contraction of isolated heart changed equivocally. In concentration 70 microM ADP-ribose in 50% of cases produced biphasic action: negative inotropic effect was preceded by positive inotropic effect. In other cases this concentration exerted negative inotropic effect. In concentration 10 microM only negative inotropic effect was observed. Contrary to ADP-ribose its metabolite AMP exerted only monophasic positive inotropic effect on isolated heart. The preparations studied differed in dynamics of cardiotropic action. In experiments in vivo ADP-ribose and AMP caused monophasic negative chronotropic and monophasic positive inotropic effects.

[Comparison of anticoagulant effects of regulatory proline-containing oligopeptides. Specificity of glyprolines, semax, and selank and potential of their practical application].

Experimental and theoretical demonstration of different effect of certain regulatory peptides (RPs) on blood coagulation is available. The problem of the role of RPs in hemostatic processes becomes particularly significant since, first, the peptides are widespread in nature both in animal and plant tissues, second, there is a relationship between the peptide structure and function and, third, both natural and synthetic peptides are used in practical medicine to correct functions of some factors of the hemostatic system. Many peptide inhibitors of the primary and plasma hemostasis potentiating anticoagulant effects in the body have been described.

[Short peptide fragments with antiulcer activity from a collagen hydrolysate].

A peptide acidic hydrolysate of collagen (PHC) was obtained under conditions (4 N HCl) ensuring the predominant formation of short peptides, glyprolines. They were separated and their antiulcer activity was studied. Thirty individual peptides with molecular masses of 174-420 amu were isolated from the PHC by HPLC. The PHC was shown to predominantly contain 2- to 4-aa peptides, including PG, GP, and PGP. Experiments on rats demonstrated that, on intragastric administration at a dose of 1 mg/kg, PHC enhances the stability of the gastric mucosa to the action of ulcerogenic factors, such as ethanol and stress, and exhibits a protecting antiulcer effect. Even a lesser dose (0.1 mg/kg), which reduced ulcer area twofold, was effective in the stress model of ulcer formation. The intraperitoneal and intragastric administration of PHC at a dose of 1 mg/kg was found to exhibit a therapeutic effect in the acetate model of ulcer formation.

[ADP-ribose and cADP-ribose--endogenous regulators of cellular ionic balance. Cardiotropic effects of ADP-ribose].

Functions and possible mechanisms of action of adenosine diphosphate ribose (ADP-ribose) and its cyclic analogue--cycle-ADP-ribose (cADP-ribose)-- substances pretend to role of novel second messengers are reviewed. Possible mechanisms of ADP-ribose and cADP-ribose synthesis regulation and metabolism are analyzed. Prospective mechanisms of ADP-ribose and cADP-ribose transportation into the cell are described. ADP-ribose and cADP-ribose are considered as endogenous regulators of ionic balance (in particular regulators of calcium balance) in different tissues. Effects of ADP-ribose on isolated heart of frog and warm-blooded animal (rat), as well as on rat heart in vivo are discussed. The role of ionic channels and receptors, gated by ADP- and cADP-ribose in regulation of cardiomyocyte ionic balance in normal and pathological condition are analyzed. The possible role of purine receptors in ADP-ribose and cADP-ribose effects on heart are discussed.

A functional continuum of regulatory anxiety-enhancing peptides. The search for complexes providing the optimal basis for developing inhibitory therapeutic agents.

Regulatory peptides are actively involved in controlling most physiological processes. One such function is regulation of the level of anxiety and panic states. We report here a meta-analysis of data published from 1960 to 2004 on the effects of anxiety-enhancing regulatory peptides. The resulting database was used to investigate the organization and functioning of the anxiogenic regulatory peptide system. Using vector representation of the effects of these peptides, the spectra of physiological effects which might be provoked by each anxiety- and fear-increasing regulatory peptide alone and in combination were evaluated. Complexes of regulatory peptides with anxiogenic profiles with the greatest potential for the further experimental development of inhibitory pharmacological agents were identified.

[Effectiveness of ultrasmall doses of endogenous bioregulators and immunoactive compounds].

The data and hypotheses on the mechanisms of action of ultrasmall doses (USD) and ultralow concentrations (ULC) of endogenous bioregulators and immunoactive compounds (regulatory peptides, cytokines, etc.) are presented. The reliability of the published data on the effectiveness of USD and ULC within the concentration limits 10(-13) - 10(-24) M and lower is considered.

Natural and hybrid ("chimeric") stable regulatory glyproline peptides.

The present concept of relative instability of regulatory peptides (RPs) in organisms must be amended. The recently characterized family of glyprolines and some other prolyl-glycyl-proline (PGP)-containing oligopeptides show the stability quite comparable with those of major pharmacological preparations. The ability of glyprolines to pass gastro-enteric tract barriers opens ways to per-oral administration of this new group of drugs such as semax, selank and their fragments. The most interesting approach is the creation of hybrid ("chimeric") peptide drugs combining the unmodified representatives of various natural RPs that distinctly manifest their inherent physiological activities and cooperate with each other in stabilization of whole peptide in vivo. As the result, the activity of such peptides as semax and selank may have value in a vide variety of pathological processes.

[Functional continuum of the regulatory peptides enhancing anxiety. Search for the optimal complexes as a basis for developing inhibitory therapeutic agents].

Regulatory peptides (RP) take an active part in managing the majority of physiological processes. One of these functional applications is the monitoring of the anxiety level, of panic state. This work represents the presumptive analysis of literature data of 1960-2004 on the effects of regulatory peptides enhancing anxiety (RP-AT). This information database was used for researching the characteristics of organization and functionality of the system of anxiogenic RP. Taking into account the method of vector representation of RP effects, estimation of spectra of physiological effects that can go with each of RP-AT and their combination, was carried out. The most perspective RP complexes of anxiogenic profile for further experimental development of inhibitory therapeutic agents are proposed.