Effect Of Semax Research Articles

Semax as a modulator of the psycho-emotional status of rats in an experimental model of depression based on stress

In modern physiology, the priority direction is the study of the influence of various types of stress, leading, as a rule, to the development of depressive states, on the physiological systems of the body. The main methods for assessing the neuroprotective effect, which is the main component of defense against stress, include the study of behavioral reactions that reflect motor, emotional, and cognitive changes. The study of drugs based on regulatory peptides is promising. Semax (ACTH4-7PGP) is a representative of a new synthetic peptide engineering, practically devoid of a hormonal effect and completely preserving the neurotropic activity of adrenocorticotropic hormone. The aim of the work was an experimental study of the effect of semax on the behavior of animals under the influence of experimental depression based on “social” stress. Material and methods. The study was carried out on 50 outbred male rats aged 6 months. Semax effects were studied under conditions of sensory contact - a model of experimental depression based on the formation of aggressive and submissive behavior in animals, using the multicomponent model the Suok test (“ropewalking”) and the Porsolt test to assess the depressive behavior of rats. Results and its discussion. Intermale confrontations led to a decrease in the time spent in the light half of the test, the number of “exploratory” downward glances, directional head movements; a decrease in the number of visited segments in the light section in victims and aggressors. As a whole, the study of behavioral reactions in animals in the Suok test and the Porsolt test in the model of experimental depression (sensory contact) showed the formation of an anxious-depressive state in animals, which was confirmed by a decrease in the motor and exploratory activity of rats. The results were obtained during the Porsolt test, indicating the formation of a depressive state in animals, which was confirmed by an increase in the total period of immobility in both aggressors and victims, an increase in the time of passive swimming, and a decrease in the time of active swimming. With a comprehensive assessment of animal behavior indicators in the Suok test, against the background of a decrease in the level of anxiety under the influence of semax, an improvement in the parameters of exploratory behavior was observed, in the Porsolt test – of motor activity indicators. Conclusions. Investigation of semax effect on the behavioral reactions of animals under conditions of sensory contact indicates that this drug exhibits an anxiolytic and antidepressant effect, eliminating pathological changes in the psycho-emotional status of animals.

Paradoxical Effect of Combined Exposure of Semax and Ammonium Molybdate on Learning and Memory of Rats

The combined effect of semax with aqueous solutions of lead diacetate (10-7 M) and ammonium molybdate (10-5 M) on the formation of a conditional two-way avoidance reaction in rats in a shuttle chamber was studied. It was found that both heavy metal salts inhibit learning and memory; lead diacetate caused greater depression. Semax slowed down the production of the conditional reaction, but counteracted the negative influence of both metals on this process. At the same time, the influence of semax on the formation of the avoidance reaction in the presence of ammonium molybdate, which in itself inhibited avoidance, paradoxically intensified. With the combined effect of the peptide and ammonium molybdate, the formation of a conditional reaction occurred much faster than against the background of semax without combination with molybdenum. In general, the data obtained indicate that semax counteracts the neurotoxic effect of lead and molybdenum salts. Since the main mechanism of the neurotoxic effect of heavy metals is oxidative stress, the indicated positive effect of semax can, in our opinion, serve as confirmation of the presence of antioxidant properties in the spectrum of pharmacological activity of the peptide.

Cognitive function restoration in rats with chronic brain ischemia using Semax and hopantenic acid comprehensive administration

The relevance and importance of treating patients with ischemic brain lesions are indisputable. Chronic ischemic processes in the brain occur much more frequently than acute cerebral circulation disorders, leading to prolonged disability and being the main contributors to a significant number of strokes. Cognitive dysfunctions prevail in the dynamics of the post-ischemic period and are often the primary determinants of the severity of residual organic and subsequent functional impairments of the brain. The aim of the study is to investigate the effectiveness of separate and combined administration of Semax and hopantenic acid in the pharmacological correction of cognitive disorders in rats with experimental chronic brain ischemia. It has been established that rats with chronic brain ischemia exhibit cognitive impairments from the 1st day, manifested in worsened learning processes, short-term and long-term memory functioning in the context of conditioned active avoidance and conditioned feeding reflexes. It has been shown that separate and combined application of Semax and hopantenic acid contributes to the restoration of the learning process and improvement of mnestic functions in rats with chronic brain ischemia. The most pronounced nootropic effect in rats with chronic brain ischemia was registered under the conditions of combined administration of Semax and hopantenic acid, starting from the 3rd day of the study. Subsequently, in terms of anti-ischemic efficacy, the effect of Semax follows, which was realized starting from the 3rd day of the study. The least pronounced neuroprotective effect belongs to hopantenic acid, starting from the 7th day of the study. The author considers the obtained data as experimental groundwork for the feasibility of clinically testing the nootropic effects of the combined administration of Semax and hopantenic acid in cases of chronic brain ischemia. The comprehensive pharmacological correction of cognitive disorders in chronic brain ischemia is pathogenetically justified and aimed at activating sanogenetic mechanisms.

Influence of Semax on the Level of Pro- and Anti-Inflammatory Cytokines in Conditions of "Social" Stress

Introduction: This study was devoted to the experimental study of the effect of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the level of pro- and anti-inflammatory cytokines (IL-1β, IL-4, IL-6, TNF-α, TGF-β1) in conditions of "social" stress Aim of the study: to study the effect of Semax on the level of pro- and anti-inflammatory cytokines (IL-1β, IL-4, IL-6, TNF-α, TGF-β1) under conditions of “social” stress. Materials and methods: White nonlinear rats (males, 6–8 months of age) were used as experimental animals. The animals were divided into groups: 1 – the control group (n=10); 2 – animals exposed to "social" stress (20 days) (n=10 aggressors/10 victims); 3 – rats exposed to "social" stress and receiving Semax intraperitoneally at a dose of 100 μg / kg / day (20 days) (n=10 aggressors/10 victims). Sensory contact was chosen as an experimental model of "social" stress. The level of cytokines (IL-1β, IL-4, IL-6, TNF-α, TGF-β1) was determined by the method of enzyme-linked immunosorbent assay. Results: Currently, within the framework of the development of a direction to study the functioning of the unified cytokine network of the body, there is a need for a detailed analysis of changes in the production of individual cytokines during various pathophysiological reactions, including stressful effects. The experimental "social" stress is accompanied by an increase in the production of IL-1β, IL-6, TNF-α, TGF-β1, which allowed us to consider stress as the main inducer of the production of cytokines of the family of proinflammatory interleukins and various growth factors. It was previously thought that inflammation and the immune response are the only factors capable of causing the production of most cytokines. In recent years, scientific works have appeared in which stress occupies an important place among the inducers of cytokine production. This fact has been confirmed by our experiments. Experimental "social" stress is accompanied by changes in the production of IL-1β, IL-4, IL-6, TNF-α, TGF-β1, which allowed us to consider stress as the main inducer of the production of proinflammatory cytokines and growth factors. Conclusion: Evaluation of the effect of Semax on the level of cytokines under conditions of "social" stress showed that the effect of Semax is aimed at restoring the level of the studied cytokines in the group of stressed animals.

Effects of Semax in the Rat Models of Acute Stress

Effects of Semax in the Rat Models of Acute Stress

Effects of Semax in the Models of Acute Stress

Acute stress exposure causes a cascade of neurochemical reactions, leading, in particular, to a change in behavior and increased tolerance to pain in humans and animals. ACTH/MSH-like peptides play an important role in regulating the body’s response to stressful exposures. The aim of the present study was to assess the effects of the ACTH4–10 analogue heptapeptide Semax in various models of acute stress. The effect of intraperitoneal Semax administration at doses of 0.05 and 0.5 mg/kg on changes in behavior and pain sensitivity of Wistar rats in models of inescapable intermittent foot shock stress and forced cold-water swim stress was investigated. To assess the involvement of the endogenous opioid system in the effects of stress, an impact of pretreatment with opioid receptor antagonist naloxone (1 mg/kg) was studied. The stressors used led to an increase in the pain threshold in the paw-pressure test, which indicates the development of stress-induced analgesia (SIA). In addition, rats exposed to stress had an decrease in exploratory behavior and an increase in the anxiety-like behavior in the hole board test. Both Semax and naloxone attenuated SIA in the model of inescapable foot shock stress, but did not affect the value of the pain threshold in the model of forced cold swim stress. Both studied drugs did not affect the behavior of rats in the models of acute stress used. It can be concluded that Semax blocks the opioid form of stress-induced analgesia, but does not affect the behavioral alterations in rats exposed to acute stress.

Correction of hypertensive retinal changes in rats with Semax

Currently, there are no drugs for the specific treatment of hypertensive retinal changes. The main therapy is for the treatment of a systemic disease – hypertensive disease. Therefore, the search for ways of specific pharmacological correction of hypertensive retinal changes is of great interest. The aim of the study: To evaluate the correction possibility of retinal injuries with Semax in a rat model of hypertensive neuroretinopathy. Materials and methods: The model was performed by injection of N-nitro-L-arginine methyl ester (L-NAME) at a dose of 1.25 mg/100 g of rat mass within 28 days and a single increase in intraocular pressure (IOP) to 110 mmHg for 5 min. The retinoprotective effect of Semax at a dose of 7.2 μg/100 g of rat mass, in comparison with Picamilon at a dose of 3 mg/100 g of rat mass, was estimated by laser Doppler flowmetry (LDF) and electroretinography (ERG). Results: The use of Semax led to an increase in retinal perfusion by 62.7%, p < 0.05, in comparison with the group with the model, and by 9.9%, p < 0.05, in comparison with Picamilon; an increase in the b/a coefficient by 31.4% in comparison with the group with the model, p < 0.05, and by 14.6%, p < 0.05 in comparison with Picamilon. Conclusion: The neuroretinoprotective effect of Semax in correction of hypertensive retinal changes in rats may be due to the presence of neuroprotective, neurometabolic, antioxidant and endothelioprotective effects in Semax. Thus, Semax can be a promising agent in hypertensive neuroretinopathy treatment.

Brain Protein Expression Profile Confirms the Protective Effect of the ACTH(4-7)PGP Peptide (Semax) in a Rat Model of Cerebral Ischemia-Reperfusion.

The Semax (Met-Glu-His-Phe-Pro-Gly-Pro) peptide is a synthetic melanocortin derivative that is used in the treatment of ischemic stroke. Previously, studies of the molecular mechanisms underlying the actions of Semax using models of cerebral ischemia in rats showed that the peptide enhanced the transcription of neurotrophins and their receptors and modulated the expression of genes involved in the immune response. A genome-wide RNA-Seq analysis revealed that, in the rat transient middle cerebral artery occlusion (tMCAO) model, Semax suppressed the expression of inflammatory genes and activated the expression of neurotransmitter genes. Here, we aimed to evaluate the effect of Semax in this model via the brain expression profiling of key proteins involved in inflammation and cell death processes (MMP-9, c-Fos, and JNK), as well as neuroprotection and recovery (CREB) in stroke. At 24 h after tMCAO, we observed the upregulation of active CREB in subcortical structures, including the focus of the ischemic damage; downregulation of MMP-9 and c-Fos in the adjacent frontoparietal cortex; and downregulation of active JNK in both tissues under the action of Semax. Moreover, a regulatory network was constructed. In conclusion, the suppression of inflammatory and cell death processes and the activation of recovery may contribute to the neuroprotective action of Semax at both the transcriptome and protein levels.

The Peptide Drug ACTH(4-7)PGP (Semax) Suppresses mRNA Transcripts Encoding Proinflammatory Mediators Induced by Reversible Ischemia of the Rat Brain

Due to its nootropic, neuroprotective, and immunomodulatory effects, the peptide Semax is utilized in the treatment of ischemic stroke. Our earlier RNA-Seq analysis of the transcriptome in an ischemic model of transient occlusion of the middle cerebral artery showed an increase in the mRNA levels of many proinflammatory genes, and the suppression of their induction by Semax. However, for many relevant genes, including Il1a, Il1b, Il6 and Tnfa, the levels of their expression were too low for detailed quantitative evaluation. Here we utilize qRT-PCR to analyze the effects of the Semax peptide on the expression of weakly expressed mRNAs encoding several proinflammatory mediators, and show that exposure to Semax leads to a statistically significant decrease in the Il1a, Il1b, Il6, Ccl3, and Cxcl2 mRNAs, which compensates for the increase in the transcription of these genes induced by ischemia-reperfusion. We conclude that the observed protective effect of Semax in the model of stroke may be due to its anti-inflammatory effects. We also discuss the limitations of the RNA-Seq when applied to quantifying less abundant transcripts as compared to the real-time RT-PCR method.

The Influence of Selank on the Level of Cytokines Under the Conditions of "Social" Stress.

It was previously thought that inflammation and an immune response were the only factors capable of causing IL-1β, IL-6 and other cytokine`s production. In recent years data have appeared that stressful effects can also occupy an important place, enhancing production of IL- 1β, IL-6 and other cytokines; the result will be a change in the functional activity of a particular cell element, for example immunocompetent cells with subsequent development of inflammation, or a change in the functional activity of neurons. This experiment is aimed at studying the effect of the Selank glyprolin neuropeptide drug on the level of cytokines in animals under conditions of "social" stress, the results of which indicate the presence of stress-protective activity. White nonlinear rats were used as experimental animals. A model of confrontations between males was chosen to create a "social" stress. The animals were in pairs in a cage which were separated by a septum preventing physical contact but having openings that provide sensory contact. Each day, the septum was removed for 10 minutes leading in an overwhelming majority to agonistic collisions (confrontations). Laboratory animals were divided into 3 groups: a group of intact males, a group of animals that were subjected to stress (sensory contact) for 20 days and a group that received intraperitoneally Selank at a dose of 100 mcg/kg/day under conditions of 20-day stress. The level of cytokines under study was determined by enzyme-linked immunosorbent assay. As a result of the work performed to determine the concentration of pro-inflammatory and anti- inflammatory cytokines, it was found that in the serum of animals exposed to stress, there was a statistically significant increase in the level of IL-1β, IL-6 and TGF-β1 in individuals with both types of behavior. It should be noted that, under the conditions of this stressful impact, there was a tendency to decrease the concentration of IL-4 and increase the level of TNF-α but these indicators were not statistically significant. Evaluation of the effect of Semax on the level of the cytokines in a stress-induced state showed that this neuropeptide causes a decrease in the concentration of IL-1β and IL-6, restoration of the level of IL-4, as well as suppression of the production of TGF-β1 and TNF-α in these conditions. This peptide is able to reduce the concentration of IL-1β, IL-6 and TNF-α, as well as TGF-β1, practically reaching control values, when studying the effect of Selank on the level of cytokines under conditions of " social" stress. There is the need for a detailed study of the role of cytokines in the development of stress-induced changes in order to find optimal correction tools.

Composition of Colon Microbiota in Rats Treated with ACTH(4-7)-PGP Peptide (Semax) under Conditions of Restraint Stress.

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.

The Administration of Semax and HLDF-6 Peptides to Rats Regulates Protein Synthesis Rhythm in Hepatocytes and Corrects Senescent Disturbances

To clarify the organizing effect of Semax and HLDF-6 peptides on the kinetics of protein synthesis in hepatocytes, in addition to an in vitro study (Brodsky et al., 2019), the effects of these peptides in vivo have been studied. The circahoralian (ultradian) rhythm of protein synthesis, that is, a marker of the direct cell-to-cell communication, was investigated in rats of different ages. Peptides were injected intraperitoneally into young (2–3-month-old) or old (1.5–2-year-old) rats at a 50–100-µg/kg dose. Hepatocytes were isolated and sparse or dense cultures were established. In sparse cultures from young rats that received one or another peptide, the rhythm of protein synthesis was observed; in the cultures from rats of the same age that were injected with saline, no rhythm was found. In dense cultures of old rats after the action of the peptide, the amplitudes of the rhythm of protein synthesis did not differ from the rhythms observed in young rats; after saline injection, the rhythm amplitudes were twice as low. Injection of the peptide into adult rats that had previously received dopamine caused a protein synthesis rhythm characteristic for rats of this age; the administration of dopamine abolished the rhythm. The synchronizing effect of the peptides was maintained for at least 2 days after their single administration to the rat. The use of Semax or HLDF-6 is recommended to compensate for the disturbances of the kinetics of protein synthesis in humans in aging and pathology.

INFLUENCE OF SEMAX ON THE LEVEL OF INTERLEUKIN-1βIN THE CONDITIONS OF “SOCIAL” STRESS

A study on the effect of Semax on the level of interleukin-1β under conditions of “social” stress was performed on non-white white rats-males. The formation of a stress reaction under the conditions of “social” exposure was confirmed by the presence of a “stress triad”, including adrenal hypertrophy, a decrease in the number of eosinophils in the peripheral blood and the presence of erosive and ulcerative lesions of the gastric mucosa. The level of serum IL-1β was determined by the method of enzyme-linked immunosorbent assay (ELISA). “Social” stress, formed as a result of inter-male confrontations, is accompanied by an increase in cytokine production, manifested by an increase in the concentration of interleukin-1β. Against the background of Semax administration to stressed animals, we can speak of this representative from the group of neuropeptides, as a possible means of correction, contributing to a decrease in the level of IL-1β.

INFLUENCE OF SEMAX ON THE INTENSITY OF LIPID PEROXIDATION IN IMMUNOCOMPETENT ORGANS IN THE CONDITIONS OF “SOCIAL” STRESS

This study is devoted to an experimental study of the effect of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the intensity of lipid peroxidation of the thymus and spleen lipids of male rats under conditions of “social” stress. “Social” stress in animals was modeled by the formation of aggressive and submissive behavior of males in the conditions of distant sensory contact. The intensity of lipid peroxidation (LPO) in the thymus and spleen was determined by spectrophotometry using three indicators: the initial level of products reacting with thiobarbituric acid (TBA-reactive products), the rate of spontaneous and induced by ascorbate and iron ions of LPO. “Social” stress is accompanied by an increase in peroxidation processes in immunocompetent organs, which contributes to the development of stress-induced functional disorders of the immune system. Against the background of Semax administration under “social” stress, its pronounced corrective effect on lipid peroxidation rates is observed, as evidenced by a decrease in spleen and thymus tissue homogenates of male rats in the initial level of TBA-reactive products, as well as spontaneous and ascorbate-dependent levels of lipid peroxidation.

Стресс-протекторное и иммуномодулирующее действие Семакса в условиях экспериментального информационного стресса

Objective: to study the stress-protective and immunomodulatory effects of Semax under conditions of informational stress. Materials and methods. The study deals with stress-protective and immunocorrective effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) under conditions of experimental informational stress which was performed on white non-linear male rats. The formation of a stress reaction under the conditions of informational impact was confirmed by the presence of a stress triad, including adrenal hypertrophy, a decrease in the number of eosinophils in the peripheral blood and the presence of erosive-ulcerative lesions of the gastric mucosa. In addition, to assess the reactivity of the organism, the adaptation intensity index according to L.Kh. Garkavi was used as an indicator of the balance of the response of blood cells to the stress factor. Functional activity of the immune system of laboratory animals was assessed on the basis of standard immunopharmacological tests: delayed-type hypersensitivity reaction (DTH), direct agglutination test (DAT), latex test for studying the phagocytic activity of peripheral blood neutrophils, evaluation of changes in the leukocyte formula. Results. It has been established that under conditions of information stress, changes in the immune response are multidirectional that confirms the theory of “immune imbalance” under the action of stress factors. As a result of studying the influence of Semax under conditions of informational stress, it was found that the drug manifested itself as an effective stress protector and immunocorrector, reducing stress-reactive manifestations, restoring cellular and humoral immunogenesis, as well as neutrophil phagocytic activity. Conclusion. This study expands the scientific research base in the field of immune reaction under stress-induced conditions, with the aim of further developing a pharmacological strategy for correcting the revealed violations by means of substances of a neuropeptide structure.

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.

Semax as a Universal Drug for Therapy and Research

In this review, based on published experimental and clinical data (1980‒2016), a comparative analysis of the structures and effects of Semax (peptide drug) and its analogue fragments was carried out. The effect of these oligopeptides on various body systems is examined. The multiple effects of Semax for a number of diseases have been collected for a single scheme of corrective processes. The rationale for the long-term therapeutic effects of this peptide drug is presented. A comparative analysis of the temporal dynamics of the expression of certain genes is carried out.

Effects of Semax on the Default Mode Network of the Brain.

The effects of nootropic drug Semax on the neuronal network of the brain were studied by the resting state functional magnetic-resonance imaging (resting state fMRI). The study was carried out on two groups of healthy volunteers (11 men and 13 women aged 43.9±9.5 years). Resting state fMRI was carried out 3 times: directly before and 5 and 20 min after intranasal 1% Semax (14 subjects) or placebo (10 subjects). The topography of the resting state default mode network was studied. A greater volume of the default mode network rostral (medial frontal cortex) subcomponent was detected in the Semax group in comparison with controls. Resting state fMRI confirmed Semax effects on the neuronal network of the brain and demonstrated topography of these effects.

The Protective Effect of Semax in a Model of Stress-Induced Impairment of Memory and Behavior in White Rats

The effect of acute restrained stress on cognitive functions and anxiety-like behavior in white rats has been studied; furthermore, the influence of the fragment ACTH(4–10) analog Semax on the stress effects was evaluated. It was shown that stress exposure leads to impaired retention of previously acquired food-motivated maze task as well as reduced anxiety-like behavior in the elevated plus maze in rats. Preliminary intraperitonial administration of Semax (0.1 mg/kg) attenuates cognitive impairment caused by acute restrained stress, but it does not affect stress-induced changes in anxiety.

Changes in Sympathetic Innervation of the Heart in Rats with Experimental Myocardial Infarction. Effect of Semax.

The effect of peptide Semax on remodeling of cardiac sympathetic innervation was examined in rats with experimental myocardial infarction. In 28 days after ischemia/reperfusion injury, Semax diminished the growth of sympathetic innervation of ventricular septum, although it produced no effect on the density of β1 and β2 adrenoceptors.