Semax (MEHFPGP) increases of gastric mucosal homeostasis to such ulcerogenic factors as ethanol and stress. On stress ulcer model Semax and its two metabolites — HFPGP and FPGP in the wide range of doses — 0,06—3,7 mkmol/kg show protective antiulcer properties. On ethanol ulcer model only Semax in both of used doses (0,06 and 0,37 mkmol/kg) demonstrates reliable protective antiulcer property. It was supposed that Semax’s gastroprotective activity concerning of peripheral mechanisms of ulcerogenese did not depend on its metabolites. On the contrary to this fact Semax’s gastroprotective activity connected with central mechanisms of ulcerogenesis may be caused and gastroprotective activity of HFPGP and FPGP.

Direct correlation of the cytokine gene expression level in peripheral blood mononuclear cells (BMNCs) and gastric mucosa (GM) cells with the development of gastric ulcers of various etiologies was shown for the first time. Ethanol-induced ulceration causes an increased transcription of IFNa, IL-8, and IL-12 mRNA in BMNCs. GM damages caused by water immersion stress were accompanied by an increased transcription of TNFa. The sizes of acetate-induced damages were positively correlated with the expression of IL-10 and IL-8 genes in BMNCs and with the expression of IFNa, IL-2, IL-12, and TNF genes in GM cells. Intranasal administration of Pro-Gly-Pro (PGP) reduced ethanol-induced ulceration, activating the transcription of IFNγ, IL-2, and IL-4 mRNA in BMNCs and prevents the formation of stress- and acetateinduced ulcers by inhibiting the expression of IL-8 and IL-10 genes, respectively.

The influences of PGP on compound 48/80-induced anaphylactoid reaction development in mice and on histamine secretion from rat peritoneal mast cells (RPMC) were investigated. Anaphylactoid reaction was induced by intraperitoneal injection of compound 48/80 into mice. The amount of histamine secreted by RPMC was evaluated. Injection of PGP 15 min before injection of compound 48/80 led to decrease of mortality, and some of anaphylactoid reaction symptoms reduced. PGP had no effect on compound 48/80-induced histamine secretion from (RPMC) in vitro.

We have studied the effects of glyprolines PGP and N-acetyl-PGP on cytokine gene expression during stress and acetate-induced ulceration. Levels of RNA in mononuclear cells in circulating blood were evaluated using reverse transcription polymerase chain reaction. Intranasal administration of PGP (3.7 μmol/kg) has had a significant protective effect against stress-induced (59.4%) and acetate-induced (78.5%) ulceration in rats. N-acetyl-PGP has not changed the area of stress-induced damage, but it tended to inhibit the development of acetate ulcers. We found that stress-induced damage of gastric mucosa is accompanied by an increase in TNFα transcription and a decrease in IL-4 transcription. The development of acetate ulcers is accompanied by a decrease in expression of a number of cytokines: IFNα, IFNγ, IL-2, IL-4, IL-6, IL-12, and TNFα. The protective effect of PGP is accompanied by an increase in expression of IL-6. When N-acetyl-PGP is administered, an increase in the expression of Th-1 and Th-2 cytokines have been observed: IFNα, IFNγ, and IL-4.

The effects of glyprolines (PGP and N-acetyl-PGP) on the expression of cytokine genes in the ethanol ulcer formation model have been investigated. Determination of the activity of mRNA in peripheral blood mononuclear cells has been performed using methods of reverse transcription and polymerase chain reaction. It has been shown that, in control animals, the formation of ethanol damages of gastric mucosa in some cases is accompanied by inhibition of transcription of IFN-α, IL-6, IL-12, and TNF-α and increased transcription of IFN-Γ, IL-8, IL-10. PGP reduces the injury area by 38%, which is accompanied by significantly increased gene expression of IL-1β. The peptide Ac-PGP does not change the area of ethanol ulcers but inhibits the transcription of IFN-α, TNF-α (p < 0.05), and IFN-Γ. Thus, the gastroprotective effect of PGP is probably mediated through IL-1β.

Injection of substance 48/80 to rats led to dysfunction of mesenteric lymphatic microvessels, in particular inhibition of their contractility and modification of their reaction to norepinephrine. Injection of PGP peptide before and after substance 48/80 alleviated these disorders. The results indicated the possibility of peptide correction of lymphatic vessel dysfunction.

The development of inflammation (experimental model of peritonitis induced by administration of sodium thioglycolate) was accompanied by a decrease in osmotic resistance of erythrocytes. Changes in osmotic resistance of erythrocytes associated with preliminary (15 min before induction of inflammation) administration of peptide Pro-Gly-Pro were significantly weaker, and the percentage of hemolyzed cells was reduced. The peptide injected against the background of developed inflammation (1 h 45 min after induction) had no corrective effect on osmotic resistance. During in vitro experiments, Pro-Gly-Pro did not affect hemolysis of intact erythrocytes. These results support the assumption that prophylactic administration of the peptide protects erythrocyte membranes and increases their osmotic resistance.

Tripeptide Pro-Gly-Pro interacted with dopamine receptors in vitro and reduced behavioral manifestations of apomorphine-induced hyperfunction of the dopamine system in verticalization, stereotypy, and yawning tests. Presumably, the behavioral effects of Pro-Gly-Pro tripeptide were mediated through post- and presynaptic D 2 and D 3 receptors.

The investigation of the effect of peptide prolyl-glycyl-proline (PGP) on β-hexosaminidase and histamine secretion by mast cells in primary culture has shown that incubation of mast cells with PGP (6 × 10 −5 M) before their activation by synacten significantly decreased the amount of secreted histamine and β-hexosaminidase in comparison with the action of synacten only. The peptide in investigated concentration had no influence on the level of spontaneous secretion. Incubation of cells with PGP did not prevent their activation by compound 48/80. Therefore, PGP can have a direct effect on isolated rat mast cells in vitro and diminish their secretory activity under activation by synacten.

The influence of PGP on compound 48/80-induced anaphylactoid reaction development in mice and on histamine secretion from rat peritoneal mast cells (RPMS) under their activation by compound 48/80 were investigated. Anaphylactoid reaction was caused by intraperitoneal injection of compound 48/80 into mice. The number of animals with manifestations of anaphylactoid reaction symptoms, the severity of these symptoms, the amount of died animals and the time of death were registering during an hour. Mast cells for in vitro investigations were obtained from rats’ peritoneal cavity. Secreted histamine was evaluated from formation of fluorescent product of it’s condensation with ortho-phthalaldehyde. The preventive injection of PGP in mice (15 min before compound 48/80) decreased the mortality rate of animals and intensity of anaphylactoid reaction symptoms. But PGP had no effect on histamine secretion from mast cells under their activation by compound 48/80 in vitro. Results show that there is a component in the mechanism of PGP protective effect under anaphylactoid reaction which is not connected with mast cells stabilization.

PGP, as well as GPGPGP remain stable after 24-hour incubation in a proteolytic environment (in vitro), like equine and rat gastric juice, hydrochloric acid and pepsin in the solution of hydrochloric acid. Perhaps the appearance of PGP's metabolites--PG and GP, that found in the stomachic tissues, is associated with the action of tissue and blood peptidases. Thus, the effects of PGP and GPGPGP cause by the influences both of the peptides and their metabolites, that agree with previously results.

The decrease in the severity of erosions and ulcer lesions after preventive treatment with PGP or PG correlated with a decrease in the content of lipid peroxidation products to a control level. Activities of SOD and catalase also returned to control values. GP produced the weakest effect on pro-and antioxidant state of the gastric mucosa. We concluded that the pronounced preventive effect of PGP and PG on the development of ethanol-induced erosions and ulcer lesions is largely determined by their antioxidant properties. Glyprolines can be considered as a promising means for prevention and treatment of stomach and duodenal ulcers.

Pro-Gly-Pro and its metabolite Gly-Pro effectively prevented the development of erosive and ulcerative lesions of the gastric mucosa in rats under conditions of water-immersion restraint stress by restoring the oxidatant-antioxidant balance in the total fraction of gastric mucosa cells. Pro-Gly was least effective in this respect. We conclude that glyprolines hold much promise as pharmaceutical products, which can be used in gastroenterological practice for the prevention and therapy of ulcer disease of the stomach and duodenum.

We studied the effect of acute (single immobilization for 1 h) and repeated (daily immobilization for 1 min, 5 days) moderate stress on disturbances in contractility of mesenteric lymphatic vessels in rats with experimental peritonitis. Acute stress was shown to potentiate, while moderate repeated stress attenuate the effect of inflammatory stimulus. It can be hypothesized that moderate repeated stress improves adaptive capacities of the organism, which manifests in reduction or prevention of dysfunction in contractile activity of lymphatic vessels.