Peptide derivatives of dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) acylated with lauric acid (LA) and oleic acid (OA), including LA-Gly-Pro-DA, LA-Gly-Pro-5-HT, OA-Gly-Pro-DA, and ...OA-Gly-Pro-5-HT, were synthesized. A mass spectrometric method for assessing the content of the DA and 5-HT derivatives in phosphate buffered saline (PBS Am-E404 – 100, pH 7.4) was developed. It was shown that these compounds could penetrate through artificial membranes. A special mixture of these compounds was used for modeling a situation where the molecules of DAand 5-HT derivatives diffused through the membrane as a result of their competitive interaction, which allowed a reliable determination of which compounds in the mixture penetrated more easily through artificial membranes. The comparative permeability of the blood–brain barrier (BBB) was evaluated by the method of parallel artificial membrane permeability assay (PAMPA). It was established that derivatives LA-Gly-Pro-5-HT and LA-Gly-Pro-DA, which were acylated by LA, were most promising for overcoming the BBB.
Tetrapeptide KKRR, corresponding to the ACTH
15-18
sequence, is the shortest fragment with high-affinity binding with the ACTH receptor; it does not activate this receptor and prevents the whole ...hormone molecule from binding to it, and thus exhibits the properties of an ACTH receptor antagonist. The aim of the present work was to study the effects of peptide ACTH
15-18
(KKRR) and its analog ACTH
15-18
PGP on behavior in Wistar rats in normal conditions and after acute stress produced by inescapable electrical foot shock. The peptides studied here did not affect the anxiety levels in white rats in normal conditions. Prior administration of ACTH
15-18
(250 μg/kg) and its analog ACTH
15-18
PGP (50 and 250 μg/kg) decreased anxiety and corticosterone release in rats which had received a acute electrical foot shock stress. The extent and duration of the anti-stress effects of ACTH
15-18
PGP were significantly greater than the extent and duration of the effects of its natural prototype.
We studied the effect of Semax on the state of intestinal microbiota in rats subjected to restraint stress. Semax was injected to Wistar male rats intraperitoneally in doses of 5, 50, 150, 450 μg/kg ...12-15 min before modelling chronic restraint stress. It was found that stress exposure reduced the number of obligate bacteria in the colon microbiota, but increased the content of opportunistic microorganisms. Semax in doses of 50 and 150 μg/kg prevented the stress-induced changes in the composition of colon microbiota. The observed effects of Semax might be mediated by the central neurotropic effects as well as by binding to peripheral melanocortin receptors of the intestine.
We studied immunocorrecting effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the model of “social” stress caused by sensory contact and intermale confrontation. Functional activity of the immune ...system of laboratory animals was evaluated in standard immunopharmacological tests: delayed-type hypersensitivity reaction, direct agglutination test, latex test for studying phagocytic activity of peripheral blood neutrophils, changes in differential leukocyte count, and weight of immunocompetent organs. It was found that changes in the immune response caused by “social” stress are multidirectional, which confirms the theory of stress-induced “immune imbalance”. Semax acted as effective immune corrector restoring cellular and humoral immunogenesis reactions and phagocytic activity of neutrophils. This attested to the presence of immunomodulating properties in Semax and necessitates further studies in this field.
Short endogenous peptides represent one of the most important constituents of the mammalian body's general regulatory system. Some synthesized analogs and modified natural peptides (eg, ...corticotropins) also show high biological activity. Nevertheless, the mechanism of action of regulatory peptides remains unclear. To explain the effects of peptides of intermolecular processes, the hypothesis that a synactonal mechanism underlies the action of regulatory peptides, exemplified by the heptapeptide Semax, has been proposed. Thus, in the total pool of Semax metabolites, which includes the cleavage products of the parental molecule, we can distinguish the functional core, represented by the major metabolic products-peptides HFPGP and PGP. These peptides have their own binding sites with similar although differing characteristics. Together with Semax, they constitute a single complex of bioregulators acting in a certain sequence and in interaction, ie, synacton. It can be assumed that the diverse clinically significant effects of the drug Semax are determined by its synacton. Specific interactions between some tritium-labeled peptides (basic constituents of the Semax synacton) and plasma membranes of neurons have been characterized. Only a few peptides of the Semax synacton showed competitive activity for the Semax binding sites. Fragments comprising 5 amino acid residues (EHFPG and HFPGP) showed the highest competitive activity. We also characterized the processes of specific ligand-receptor interactions of some tritium-labeled corticotropins (
H-ProMEHFPGP,
H-ProHFPGP, and
H-ProPGP) by applying mathematical discriminative models (Scatchard, Hill, Bjerrum, and Lineweaver-Burk plots). So the intermolecular interactions of these peptides with plasma membranes of neuronal brain targets are probably not limited by specific binding at orthosteric sites. The effect of peptides that act in the synacton considerably extends the regulatory potential of the initial molecule.
Glutamate (Glu) excitotoxicity, which accompanies brain ischemia or traumatic brain injury, is the leading mechanism of neuronal death. In the present work, we studied the effects of the peptides ...HFRWPGP (ACTH
6–9
PGP), KKRRPG, and PyrRP on the survival of cultured cortical neurons on the background of excitotoxic effect of Glu (100 µM). Biochemical (MTT/WST) and morphometric analyzes showed that, depending on the dose, ACTH
6–9
PGP and KKRRPGP protect neurons from the cells death, while PyrRP, conversely, enhances it. The neuroprotective effect of ACTH
6–9
PGP is accompanied by a slowdown in the development of delayed calcium dysregulation and synchronous mitochondrial depolarization. Among the studied peptides, only ACTH
6–9
PGP significantly increased the number of neurons that restored Ca
2+
homeostasis after Glu was abolished. The influence of KKRRPGP was less pronounced, whereas PyrRP, on the contrary, reduced the number of neurons with low Ca
2+
i
. Thus, this study revealed the high therapeutic significance of ACTH
6–9
PGP and allowed assessing the prospects for its possible clinical use.
The effect of temperature, catalyst-to-NMDA ratio, and reaction time on the efficiency of deuterium incorporation into NMDA has been studied. It has been found that at temperatures above 180°С, ...incorporation of the label in NMDA changes insignificantly. The same pattern is observed when the reaction time changes. Increasing the time from 5 to 15 min increases the incorporation of deuterium by 2–3%. Reaction conditions have been selected that ensure the replacement of all protium atoms by deuterium in more than one third of NMDA molecules. It turned out to be possible to change the deuterium content in the substance by changing the deuterium-to-NMDA ratio. When deuterium gas reacted with a preparative amount of NMDA, on average of 2.76 deuterium atoms were included in the amino acid molecule.
Anticoagulant effects of 12 short peptides of the glyproline series — Arg-Glu-Arg-Pro-Gly-Pro (RERPGP), Arg-Glu-Arg-Val-Gly-Pro (RERVGP), Arg-Glu-Arg-Gly-Pro (RERGP), Arg-Pro-Gly-Pro (RPGP), ...Pro-Leu-Pro (PLP), Pro-Leu-Pro-Ala (PLPA), Pro-Gly-Pro-Leu (PGPL), Phe-Pro-Leu-Pro-Ala (FPLPA), Pyr-Arg-Pro (PyrRP), Lys-Lys-Arg-Arg-Pro-Gly-Pro (KKRRPGP), Arg-Lys-Lys-Arg-Pro-Gly-Pro (RKKRPGP), and Lys-Arg-Lys-Pro-Gly-Pro (KRKPGP) in concentrations of 10—3 and 10—2 mg/ml
in vitro
was demonstrated by the thromboelastographic method. The effects of 6 peptides ((RERPGP, RPGP, PLP, PLPA, RKKRPGP, and KKRRPGP) were also observed
in vivo
after intranasal or oral administration. Changes in the studied thromboelastographic parameters towards hypocoagulation in comparison with the control group were noted. Arginine and leucine glyprolines produced the maximum anticoagulant effect.
