Experimental Substantiation of Application of Semax as a Modulator of Immune Reaction on the Model of "Social" Stress.

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.

[PHENOTROPIL AS MODULATOR OF CYTOKINE LEVEL UNDER CONDITIONS OF EXPERIMENTAL IMMUNOPATHOLOGY].

We have studied the effect of phenotropil on the level of cytokines IL-1, IL-4, and IL-6 under conditions of immunosuppression induced by cyclophosphamide (150 mg/kg, single i.p. injection) and under immune system hyperreactivity caused by lipopolysaccharide (LPS of Pseudomonas aeruginosa, 100 gg/kg, single i.p. injection). The experiments were performed on 48 Wistar male rats aged 6-8 months. Each series was carried out according to similar schedule onree groups of animals: group 1, intact animals; group 2 received cyclophosphamide (series 1) or LPS (series 2); group 3 received phenotropil on the background of immunomodulators. Phenotropil (synthesized at the Department of Organic Chemistry of the A. I. Herzen St. Petersburg Pedagogical University) was administered in a dose of 25 mg/kg (i.p.) for 5 days, starting 2 days before the introduction of immune system activity modulatos. The levels of serum cytokines IL-1ß, IL-4, and IL-6 were determined by ELISA "sandwich" with the use of monoclonal antibodies (ELISA kits of BenderMedsystems company; instrument Uniplan AIRF-01 of Picon company, Moscow) at a wavelength of 450 nm. In case of immunodeficiency caused by cyclophosphamide, there was a significant decrease in IL-1ß, IL-4 and IL-6, but the introduction of phenotropil largely restored their levels. Upon stimulation with LPS, the immune response showed inc- rease in pro-inflammatory cytokines IL-ß, IL-6 and decrease in IL-4. Under these conditions, phenotropil restored the normal levels of IL-1ß, IL-6 and caused an increase in the level of IL-4.

[Psychomodulating activity of phenotropil in experimental hyperthyroidism].

Psychoimmunomodulating action of phenotropil has been shown on the model of experimental hyperthyroidism. It has been found that the drug (14-days i.p. injection in a dose of 25 mg/kg) is capable of restoring the cellular and humoral immunoreactivity and improve psychoemotonal state of animals by eliminating disturbances in the behavior reactions that appear as a result of the induced hyperthyroidism.

[Psycho- and immunomodulation properties of baclofen].

Psycho- and immunomodulator activity of GABA(B)-mimetic drug baclofen was studied on Wistar-line rats with the cyclophosphamide-induced immunosuppression and lypopolysaccharide-induced immune stress. It was established that the stimulation of GABA(B) receptors in animals with the immune system hypofunction favors regeneration of the cellular and humoral components of immune response. At the same time, under the conditions of immune hyperreactivity, the modulating effect of baclofen appears only in respect of the cell-mediated immune reaction. Moreover, it was shown that baclofen suppresses psychoemotional disorders that develop under the conditions of cyclophosphamide- and lipopolysaccharide-induced immunopathology. The results obtained in this study confirm that GABA(B) receptors participate in the processes of psycho- and immunomodulation.

[Phenotropyl succinate as the means for correction of neuroimmune disturbances under conditions of informational-physical stress].

In Wistar rats, psycho-immune-modulating properties of phenotropyl succinate were studied under conditions of informational-physical stress. The effect ofphenotropyl succinate on the organism specific and unspecific resistance was studied. The data obtained indicate the phenotropyl succinate ability to release neuroimmune disturbances developing under conditions of informational-physical stress.

Psychoimmunomodulatory effect of phenotropil in animals with immune stress.

We studied the effect of phenotropil (25 mg/kg intraperitoneally, 5 days) on the immune and psychoemotional state of Wistar rats with LPS-induced immune stress. Hyperactivity of the immune system in animals after treatment with Pseudomonas aeruginosa LPS (100 µg/kg intraperitoneally, 3 days) manifested in a significant increase in the delayed-type hypersensitivity index, antibody titer in the reaction of passive hemagglutination, and phagocytic activity of peripheral blood neutrophils. Locomotor, orientation, and exploratory activities were reduced, while anxiety increased in animals with immune stress. Phenotropil exhibited the psychoimmunomodulatory effect under these conditions, which manifested in prevention of anxiety and fear response, increase in horizontal locomotion and exploratory behavior, and improvement of immunoreactivity.

[GABA-ergic system and GABA-based drugs for regulation of immunogenesis].

The review summarizes available data about the influence of GABA-ergic substances on the immune system functional activity under both normal and pathology conditions. Analysis of information in the literature and publications shows that positive/inhibitory effects of GABA and its derivatives on the immune system depend on the overall background organism condition, as well as on parameters such as the level of antigenic stress. In addition, it is shown that changes in the immune reactivity achieved through the GABA-ergic system are dopamine and serotonin dependent. The immunotropic action of GABA and GABA-ergic substances is evidently determined by activating effect upon the multi-level immunogenesis control system, in particular, the GABA-sensitive receptors of the central nervous system and immunocompetent organs, as well as hypothalamo-pituitary-adrenal complex.

[Influence of GABA derivatives on some indices of lipid peroxidation in immunocompetent organs under experimental immunopathology conditions].

The effects of GABA derivatives phenotropil (25 mg/kg), phenibut (25 mg/kg), and baclofen (2 mg/kg) on the process of lipid peroxidation (LPO), as manifested by the initial level of malonic dialdehyde, velocity of spontaneous and ascorbate-dependent LPO, and the catalase activity in the homogenates of thymus and spleen, have been studied on rats of the Wistar line with cyclophosphamide (CPHA) immunodepression and lipopolysacharide (LPS) immune stress. It is established that, under the action of CPHA and LPS, activation of the LPO processes takes place in the immune organs. Under these conditions, changes of the catalase activity exhibited some specific features: in the animals under LPS action, the catalase activity increased in the spleen, while being decreased in the thymus; under the influence of CPHA, the activity of this enzyme decreased in both organs. An analysis of the antioxidant activity of GABA derivatives under the conditions of CPHA-induced immunodepression showed that all substances upon intraperitoneal introduction for 5 days favored the elimination of disturbances by suppressing the LPO processes and increasing the antioxidant protection activity. On the background of LPS-induced immune stress, all the tested substances showed a correcting action with respect to indicated biochemical processes in the thymus, while only phenibut activated the antioxidant system in the spleen.

[Immune-regulating effect of phenibut under lipopolysaccharide-induced immune stress conditions].

The immunoregulating effect of phenibut has been demonstrated on the model of immune stress caused by the injection of lipopolysaccharide from Pseudomonas aeruginosa. The degree of expression of the specific (in a delayed-type hypersensitivity reaction and passive hemagglutination) and nonspecific (phagocytic activity of neutrophils) links of immunomodulation was studied. The formation of lipopolysaccharide (LPS) induced immune stress is characterized by the increase of the indicated parameters of immunity. It is found that phenibut (under intraabdominal injection of 25 mg/kg within 5 days) removes the manifestations of hyperreactivity of the cellular link of immunity, and also restores the amount of phagocytic cells, which is evidence of the immunomodulating properties of the drug under conditions of hyperimmunization.

[Changes in the psycho-emotional state under conditions of suppressed immunogenesis, the correction of the disorders with GABA-positive means].

Behaviour and immune responses of rats and mice following cyclophosphamide administration were investigated. The psycho-immunomodulating effect of the GABAergic compounds was revealed. Phenibut (25 mg/kg) and Baclophen (10 mg/kg) restored functional activity of immune system and corrected disturbances of the behavioural responses. The GABAergic agents restored horizontal and direction investigation activities in the rats and mice, decreased grooming and increased number of passages through central zones in the "Suok" test.

[Comparative study of immunomodulating properties of phenibut and gammoxin].

Experiments on CBA mice with model immunodepression induced by cyclophosphamide showed that phenibut (25 mg/kg) and gammoxin (25 mg/kg) recover both cellular and humoral immunoreactivity and restore lymphoproliferative processes in immunocompetent organs, which is evidence for pronounced immunocorrecting properties of these drugs. A comparative analysis of the immunomodulating activity of phenibut and gammoxin showed that the latter drug predominantly affects the process of immunocompetent cell maturation (growth in mass and cellularity of thymus and spleen--the central immunocompetent organs), while phenibut mostly influences the realization of the final reaction of the primary anti-erythrocyte immune response (significant correction of local infiltration delayed-type hypersensitivity reaction and antibody formation). This difference can be related to the fact that the drugs influence GABA receptors of different types, whereby gammoxin acts on these receptors in immunocompetent organs and phenibut acts on the receptors in lymphocytes.

Comparative study of immunocorrective activity of phenibut and its organic salts in experimental immunodeficiency.

Phenibut and its derivatives normalized cellular (index of delayed-type hypersensitivity reaction) and humoral (antierythrocyte antibody titer) immunity and the lymphoproliferative processes in immunocompetent organs of animals with cyclophosphamide-induced immunosuppression. This indicates pronounced immunocorrective effects of these substances.

[Effect of baclofen on characteristics of the cellular immune response].

It has been established that GABA-B receptor agonist baclofen restores the cellular parts (the delay-type hypersensitivity reaction index, thymus weight, and thymocyte number) of immunogenesis under the experimental suppression conditions. This is probably caused both by the direct influence of baclofen on the receptors of immunocompetent cells and by the normalization of the nervous regulation of the immune response.

Some aspects of immunomodulatory effects of new benzimidasole derivatives.

Immunomodulatory activity of new condensed benzimidasole derivatives was studied in CBA mice. Some of these derivatives injected in a dose of 50 mg/kg on the day of immunization stimulated humoral and cellular elements of the primary immune response to sheep erythrocytes in mice.