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Influence of ACTG4-7-PGP (Semax) on Morphofunctional State of Hepatocytes in Chronic Emotional and Painful Stress
Abstract
We studied the effect of intraperitoneal administration of peptide ACTG4-7-PGP to male Wistar rats in doses of 5, 50, 150, and 450 μg/kg on the morphofunctional state of hepatocytes in chronic emotional and painful stress. A dose-dependent stress-limiting effect of the peptide was observed: it normalized the protein synthesis function of the liver and serum activity of ALT. The anticytolytic effect of the peptide increased with increasing its dose against the background of the increase in the relative number of multinucleated and multinucleolated cells and deceleration of the recovery of serum protein concentration. The decrease of hepatocyte cytolysis against the background of more intense morphological signs of protein synthesis processes attests to activation of reparative processes in the liver parenchyma via enhanced constitutional synthesis of protein.
... Heptapeptide Semax (MEHFPGP) is a synthetic peptide, an adrenocorticotropic hormone (ACTH) fragment analogue completely devoid of hormonal activity (Myasoyedov and Grivennikov, 2004;Levitskaya et al., 2008Levitskaya et al., , 2010Dmitrieva et al., 2010;Ivanov et al., 2017). Semax affects the processes associated with memory formation, enhances selective attention in learning and analysis of information, and improves the adaptation of the organism to hypoxia, cerebral ischemia, anesthesia, and other damaging factors. ...
In the search for stable factors regulating direct cell–cell interactions and effects on the properties of cells in aging organisms, the regulatory peptides Semax and HLDF-6 were studied. The circahoralian rhythm of protein synthesis in cells in vitro served as a marker of cell–cell interactions. The peptides normalized the cell–cell interactions, which are greatly weakened during aging. It is shown that the peptides organize the protein-synthesis rhythm in primary rat hepatocyte cultures. The effect of the HLDF-6 peptide was realized via metabotropic glutamate receptors; the blockade of these receptors by the antagonist MCPG abolished the effect of the peptide. The protein kinase inhibitor H7 prevented the effect of the peptides on the protein-synthesis kinetics. Just as for other signaling factors, the activation of protein kinases in the case of the peptides regulates the key process of direct cell–cell interactions. The effect of a single signal of each of the peptides was retained for at least 1 day. Our data allow the peptides to be recommended for improving elderly people’s condition and block the factors that disorganize the protein-synthesis kinetics.
Introduction : Tuberculosis is a widely spread infection. While treating patients for it, they are given simultaneously and for a long period 5-6 antibacterial drugs, which are, as a rule, bad for the liver. It quite often (up to 20%) causes drug-induced hepatitis. As experimental means of protecting the liver, the following peptides are suggested: chorionic gonadotropin, a recombinant drug of luteinizing hormone – luveris, and oligopeptide drugs: semax and selank.
Materials and Methods : The research was conducted on 104 outbred white male rats weighing 170-220 g. Each group included at least 10 animals. Drug-induced hepatitis was simulated through the combined 21-day administration of isoniazid, rifamycin, and ethanol. Chorionic gonadotropin, luveris, semax and selank, as well as a comparison drug mexidol, were administered once a day during the experiment. Healthy control animals and rats with drug-induced hepatitis were used as comparison groups. For evaluation of the efficiency of administered drugs, the obtained biochemical and histomorphological research data was used.
Results and Discussion : During the experiment, chorionic gonadotropin (ChG), semax and selank showed a greater therapeutic activity than mexidol and luveris. Only in the case of administering ChG, selank and semax, there was parallelism between the restoration of biochemical parameters of blood and histomorphological parameters of the liver. Administering both selank and ChG was also characterized by more active regenerative processes.
Conclusion : Administering ChG, selank and semax to patients with tuberculosis would significantly reduce the number and severity of hepatotoxic reactions.
Introduction : Drug-induced hepatitis is common in clinical practice. This problem is particularly relevant in the treatment of tuberculous infection, because for this purpose, up to 5–6 hepatotoxic drugs are used simultaneously for a long time, which often (in 15–20% of cases) leads to medical liver lesion. To protect the liver, Semax and Selank are offered – drugs of regulatory peptides group.
Materials and Methods : The research was conducted on 96 outbred white male rats weighing 180–220 g. The experimental group included about 10 animals. Drug-induced hepatitis was simulated through the combined 21-day administration of isoniazid, rifampicin and ethanol. Semax and Selank, as well as Essentiale N and Mexidol (comparison drugs) were administered once a day during the experiment. Healthy control animals with experimental hepatitis were used for comparison. Subsequently, the obtained biochemical and histomorphological parameters were evaluated.
Results and Discussion : In the experiment, Semax and Selank showed a greater therapeutic activity than the recognized hepatoprotectors – Essentiale and Mexidol. Only in the case of administering Selank and Semax, there was parallelism between the restoration of biochemical parameters of blood and histomorphological parameters of the liver. Selank was also characterized by an increased activity of regenerative processes.
Conclusion : Administering Selank and Semax to patients with tuberculosis would significantly reduce the number and severity of hepatotoxic reactions.
The stress response is a natural reaction by the body, against potentially harmful stimuli to enhance the chance for survival. Persistent activation of the chronic stress response can cause changes to homeostatic mechanisms. Immobilization/restraint stress is an easy and convenient method to induce both psychological and physical stress. Wistar strain adult albino rats were divided into two groups as non stressed group (n = 10) and stressed group (n = 10). The stressed groups were exposed to 60 days of chronic immobilization stress. At the end of the sixty day the animals were anaesthetized and blood samples were collected through cardiac puncture. The blood samples of both the groups were analyzed for selected biochemical and lipid parameters. The results were analyzed statistically by using student't test. P < 0.05 was considered as significant. Our present results showed a significant increase in the various organ weights and a significant decrease in the food intake and body weight. All the biochemical parameters [(serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), blood sugar, tissue malondialdehyde (MDA) and serum lipid profile (cholesterol, serum triglyceride (TG), low-density lipoproteins (LDL)] were significantly increased in the stressed group when compared to the non stressed group. The serum high-density lipoproteins (HDL) level did not show any statistically significant changes. The present data indicate that chronic immobilization stress causes the significant alterations in the physiological, biochemical and lipid parameters. Further the study also confirms the shift of oxidants and antioxidant balance during chronic stress.
Melanocortin system consists of native melanocortin peptides (ACTH, MSH and their fragments), melanocortin receptors (MC1R-MC5R) and their endogenous antagonists. Melanocortins have a wide spectrum of physiological activity. These peptides improve memory and attention, facilitate neuromuscular regeneration, exert neuroprotective action, affect the development of nervous system, modulate sexual behavior, have anti-inflammatory and antipyretic effects, interact with opioid system, affect the pain sensitivity and cardiovascular system, decrease food intake and body weight, influence on exocrine secretions.
The effect of ACTH4-7-PGP (Semax) intraperitoneal injection at the doses of 5, 50, 150 and 450 μg/kg b. w. on lipid peroxidation and functional hepatocytes state in Wistar male rats subjected to acute and chronic electrical foot-shock stress was investigated. It was observed that peptide at the doses of 50 and 450 μg/kg normalized malondialdehyde (MDA) level elevation in the liver homogenate caused by acute foot-shock stress. On the contrary, at the doses of 5 and 150 μg/kg Semax significantly increased MDA content without essential changes of antioxidant defense activity (catalase, superoxide dismutase, common antioxidative activity). In serum peptide at the all doses decreased stress-induced asparate aminotransferase activity elevation. In chronic stress peptide provided the normalization of protein synthetic hepatocytes function and the serum alanine aminotransferase activity with less effect on lipid peroxidation.
The aim of this study was to evaluate the effect of acute and chronic physical and psychological stressors on the induction of oxidative stress in male rat liver. Male Wistar rats were randomly divided into 3 groups as following: control, physical and psychological stress groups. Stress was induced by communication box for one (acute), fifteen and thirty (chronic) days. Once stressor periods ended, rats were anesthetized and their liver dissected out for later assessments. Exposure to physical stress enhanced liver superoxide dismutase (SOD) (19.44 %) and glutathione S-transferase (GST) (21.84 %) activities and decreased glutathione (GSH) (30.03 %) level on the 1st day (p<0.05). SOD (24.13 and 18.43 %) and GST (27.77 and 21.27 %) activities were significantly increased, while catalase activity (29.74 and 24.41 %) and GSH level (35.05 and 31.05 %) were decreased in psychological stress group after 1 and 15 days (p<0.01 and p<0.05) compared to the 1st day value in control group, respectively. Psychological stress induced an increase in liver malondialdehyde (MDA) (46 %) and plasma corticosterone (36 %) levels on the 1st day (p<0.05). However, all parameters returned to their basal value after 30 days of stress.
The results suggest that exposure to acute physical and psychological stressors induce the production of reactive oxygen species and oxidative stress in rat liver due to GSH depletion and the decreased catalase activity. The elevation of lipid peroxidation and corticosterone level in acute psychological stress may lead to more profound oxidative damage than acute physical stress. Moreover, cell protection in hepatic tissue of chronically stressed rats is indicative of possible late adaptation of the animals to stress.
We undertook these studies to explore the intracellular signaling mechanisms activated by a newly described human brain melanocortin receptor (hMC3R). Hepa cells transfected with the hMC3R gene responded to stimulation with alpha-melanocyte stimulation hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH) with dose-dependent increases in cellular content of cyclic 3',5'-adenosine monophosphate (cAMP) reaching a maximum of over 1500% of control cells at the 10(-8) M dose (EC50 = 10(-11) M). In contrast, the production of [3H]inositol phosphates in cells prelabeled with myo-[2-3H]inositol exhibited a biphasic dose-response curve with increases as high as 155% of basal at 10(-11) M alpha-MSH or ACTH, but beyond that a dose-dependent decrease was observed. The inhibitory component of the dose-response curve could be abolished by pretreatment of transfected cells with the cAMP antagonist (Rp)-adenosine 3',5'-monophosphorothioate (Rp-cAMP) or the protein kinase A inhibitor H-89. Increases in intracellular calcium induced in transfected cells by alpha-MSH in doses ranging from 10(-11) to 10(-7) M could not be observed unless the cells were pretreated with H-89. By replacing the third intracytoplasmic loop of the canine H2-histamine receptor with that of hMC3R the biphasic characteristic of agonist-induced production of [3H]inositol phosphates was conferred to the chimeric receptor. These data indicate that the hMC3R is coupled to both cAMP and inositol phospholipid/Ca(2+)-mediated post-receptor signaling systems and that the latter response is regulated by protein kinase A activity.
We discovered that simple proline-containing peptides Gly-Pro, Pro-Gly, Pro-Gly-Pro, and semax had an antistress protective
effect on the organism appearing as anticoagulation system activation. Repeated intranasal injection of each of these peptides
to rats prior to acute immobilization stress prevented a hypercoagulation response to prolonged stress lasting 60 min. At
the same time there was increase of anti-thrombotic, anticoagulant, and fibrin depolymerization activity and recovery of enzymatic
fibrinolytic activity. Dipeptides were found to have the greatest antistress effect. Our results showed that semax had a protective
effect against enhanced blood coagulability resulting from repeated immobilization stress.
We studied the effect of nootropic peptide Semaks and its inactive analog on the efficiency of UV-induced damaging of the
peritoneal macrophage plasma membrane. The increase of the time after the UV-irradiation (with doses 5 and 6 J/cm2) from 15 to 60 min led to a substantial increase in the number of damaged cells. The UV-irradiation effect has been subjected
to a substantial decrease with the adding of Semaks to the incubation medium immediately after irradiation.
The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L−/−) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L−/− and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L−/− mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot-shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses.
Upon single administration, mexidol and semax only in doses of 100 and 0.05 mg/kg, respectively, produced an antihypoxic effect on mice in the altitude chamber and hermetic chamber tests. Preventive course administration of mexidol and semax for 6 days gave significant antihypoxic effect on the model of acute hypobaric hypoxia in mice in doses of 75 and 0.1 mg/kg per day, respectively, in which the same preparations upon single administration were ineffective. Neither mexidol nor semax upon single administration were effective on the models of acute hemic and histotoxic hypoxia. On various models of amnesia (except that induced by the maximal electroshock) in mice, both mexidol and semax exhibited marked antiamnesic effects comparable with that of the reference nootrope drugs piracetam and oxyracetam. Mexidol showed a linear, while semax exhibited a bell-shaped reversible dose-effect relationships. Mexidol and semax inhibited the ortho- and antidromic population response spikes of CA1 pyramidal neurons of survival hippocampal slices in rats. It was estimated that mexidol (in contrast to semax) increased oxygen consumption in rat brain mitochondria and had a linear dose-effect relationship in a concentration range of 1-5 mM. It is concluded that mexidol should be used in high doses (for both single and course administration) for obtaining antihypoxic and antiamnesic effects, while semax requires a thoroughly controlled choice of dosage.