Selank Research & Studies

Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (р<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.

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.

The present study was aimed at the assessment of effects of anxiolytic Selank and nootropic Semax on the whole-brain resting-state functional connectivity (FC) of each of the predefined regions of interest (ROIs) in 52 healthy participants. The ROIs included amygdala (one of the key regions for the regulation of anxiety) and dorsolateral prefrontal cortex (DLPFC; the key region for executive functions, including working memory) in the right and left hemisphere. Resting-state fMRI was carried out three times, namely before, after 5 and 20 min of the injection of either Semax, or Selank, or placebo. Between-group alongwith between-condition differences were revealed in FC between the right amygdala and a region in fusiform, inferior and middle temporal as well as parahippocampal gyri in the right hemisphere. Post hoc analysis allowed us to define both general and specific effects of Selank and Semax on FC between the right amygdala and the right temporal cortex for the first time.

We studied the effects of Selank on the condition of the colon wall in Wistar male rats subjected to restraint stress. Selank was injected intraperitoneally in doses of 80, 250, and 750 μg/kg 15 min before stress exposure. In rats subjected to stress, signs of atrophy, inflammatory reaction, and changes in the number and functional activity of mast cells were observed against the background of increased corticosterone level. Selank administration led to a decrease in corticosterone levels, reduced pathomorphological manifestations of stress exposure, and accelerated adaptation. These effects were presumably realized due to multifunctional biological effects of Selank.

We studied the effects of Selank on morphological parameters of the liver in Wistar male rats subjected to chronic foot-shock stress. Selank was injected intraperitoneally in doses of 100, 300 and 1000 μg/kg 15 min before each stress session. Morphological and morphometrical analysis showed that chronic foot-shock stress induced hydropic degeneration of hepatocytes, an increase of the nucleus/cytoplasm ratio due to an increase in the area of nuclei and reduction of the cytoplasm area, the appearance of focal necroses, and lymphohistiocyte infiltration. Injection of Selank in all doses reduced the intensity of stress-induced degenerative changes. Administration of Selank in doses of 300 and 1000 μg/kg restored the nucleus/cytoplasm ratio in hepatocytes. The maximum stress-limiting effect was attained after administration of 300 μg/kg Selank.

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.05) and prevented the formation of ethanol-induced memory and attention disturbances (p<0.01) developing during alcohol withdrawal. In ex vivo experiments, Selank prevented ethanol-induced increase in BDNF content in the hippocampus and frontal cortex (p<0.05). These results indicate positive effects of the tuftsin analogue on age-related memory disturbances associated with chronic alcohol intoxication and confirm the involvement of the neurotrophin mechanism related to BDNF production into the effect of Selank.

Anxiety and mood disorders are the most abundant mental health problems worldwide. The commonly used in clinical practice anxiolytics are focused on pharmacological modulation of brain GABA receptor system activity. As a rule, their use presents a wide spectrum of clinical issues such as dependence, memory impairment and etc. There is an increasing appreciation of the role of neuropeptides and bioactive lipids in the pathophysiology of mood and anxiety disorders as "mild" agents. Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) exhibits prolonged anti-anxiety and nootropic effects.

Application of anxiolytic drug Selank to hippocampal slices increased the amplitude and discharge rate of spontaneous inhibitory postsynaptic currents in rat hippocampal pyramidal CA1 neurons. In some neurons, Selank-induced up-regulation of spontaneous inhibitory postsynaptic currents was preceded by a transient decrease in this activity. In the examined concentration range (1-8 μM), Selank demonstrated no significant dose-dependence.

It was shown that the anxiolytic effect of Selank is comparable to that of classical benzodiazepine drugs and that the basis of their mechanism of action may be similar. These data suggest that the presence of Selank may change the action of classical benzodiazepine drugs. To test this hypothesis, we evaluated the anxiolytic activity of Selank and diazepam in rats both under conditions of unpredictable chronic mild stress and in its absence, after the individual and combined administration of these compounds using the elevated plus maze test. We found that, even in the absence of chronic stress, the administration of a course of test substances changed anxiety indicators toward their deterioration, but the changes after the administration of a course of Selank were less pronounced. In conditions of chronic stress, anxiety indicator values after the simultaneous use of diazepam and Selank did not differ from the respective values observed before chronic stress exposure. The data obtained indicate that the individual administration of Selank was the most effective in reducing elevated levels of anxiety, induced by the administration of a course of test substances, whereas the combination of diazepam with Selank was the most effective in reducing anxiety in unpredictable chronic mild stress conditions.

We studied the effect of Selank administered intraperitoneally in doses of 100, 300, and 1000 μg/kg to male Wistar rats 15 min prior to restraint stress on the content of aminotransferases and total protein concentration in blood serum and intensity of free radical oxidation in the liver. Under conditions of acute restraint stress, Selank in doses of 100 and 300 μg/kg decreased catalase and superoxide dismutase activities and malondialdehyde concentration and increased total antioxidant activity in the liver homogenate. Administration of Selank in a dose of 1000 μg/kg reduced the content of aminotransferases in blood serum, decreased superoxide dismutase activity in the liver, and increased total antioxidant activity. Under conditions of chronic stress, Selank in all doses produced similar effects: reduced superoxide dismutase activity and malondialdehyde concentration in the liver tissue and AST activity in the serum. The other parameters remained unchanged.

Pharmacological effects of intraperitoneal (i.p.) and intranasal (i.n.) administration of heptapeptide selank (300 μg/kg/day for 5 days), known to possess anxiolytic and nootropic properties, were compared by studying the elevated-plus-maze behavior of inbred BALB/c and C57BL/6 mice and measuring the binding of markers to NMDA and GABA receptors of brain. The anxiolytic and nootropic efficiency of selank administered via both routes was observed only in BALB/c mice, which were characterized by initially reduced exploratory activity and higher levels of anxiety as compared to C57BL/6 mice. In BALB/c mice, i.p. selank increased the number of [G-(3)H]SR 95531 binding sites with GABA-receptors in the frontal cortex by 38%, without change in binding to NMDA receptors in the hippocampus. On the contrary, i.n. selank led to an increase in the density of [G-(3)H]MK-801 binding sites by 23% with no effect on GABA receptors. It is suggested that the differences in pharmacological spectra observed for the two routes of selank administration are determined by specific features of drug pharmacokinetics and biotransformation as well as by the dynamics of formation of the anxiolytic and nootropic effects of selank.

Clinical studies have shown the similarity of the spectrum of physiological effects of Selank and classical benzodiazepines, such as diazepam and phenazepam. These data suggest that there is a similar basis of their mechanism of action. To test this hypothesis we studied the effect of Selank and GABA on the expression of genes involved in neurotransmission. We analyzed the expression of 84 genes involved in neurotransmission (e.g., major subunit of the GABA receptor, transporters, ion channels, dopamine, and serotonin receptors) in the frontal cortex of rats 1 and 3 h after the administration of Selank or GABA (300 μg/kg) using real-time PCR method. We found significant changes in the expression of 45 genes 1 h after the administration of the compounds. Three hours after Selank or GABA administration, 22 genes changed their expression. We found positive correlation between the changes in genes expression within 1 h after administration of Selank or GABA. Our results showed that Selank caused a number of alterations in the expression of genes involved in neurotransmission. The data obtained indicate that Selank is characterized by its complex effects on nerve cells, and one of its possible molecular mechanisms is associated with allosteric modulation of the GABAergic system.

To compare the efficacy and tolerability of monotherapy with phenazepam to complex treatment with the peptide preparation selank and phenazepam in patients with anxiety disorders.

Previous studies have shown that synthetic tuftsin analogue Selank and its fragments cause a number of alterations in the expression of certain genes involved in inflammation in mouse spleen. In this work we studied the effect of Selank and its short fragment Gly-Pro on the temporary dynamics of C3, Casp1, Il2rg, and Xcr1 genes expression in mouse spleen after single intraperitoneal injection (100 μg/kg) of peptides using real-time PCR method. We found a significant 3-fold decrease in the C3 mRNA level just 30 min after Selank injection and similar alteration this gene mRNA level after Gly-Pro administration. A wave-like alteration in the Casp1 mRNA level was observed after Selank injection. We found a significant alteration in the mRNA level of the Il2rg gene at early time points after Selank and Gly-Pro administration and an almost equal reduction in the Xcr1 mRNA level 90 min after the administration of Selank and its fragment. Our results showed that, Selank and its short fragment Gly-Pro influence the expression of genes that mediate different types of immune responses, thereby maintaining the balance of the immune system. It should be noted that in most cases, there was a coincidence in the expression profiles of the studied genes after Selank and Gly-Pro administration. This might indicate an active contribution of the dipeptide to the final effect of Selank.

Previous studies have shown that synthetic tuftsin analogue Selank causes a transcriptomic response in the rat hippocampus and in spleen cells and may participate in the regulation of inflammatory processes in the body. In this work we studied the effect of Selank and two of its fragments on the expression of genes involved in processes of inflammation. We analyzed the expression of 84 genes involved in processes of inflammation (e.g., chemokines, cytokines, and its receptors) in mouse spleen 6 and 24 h after Selank single intraperitoneal injection (100 μg/kg) using real-time PCR method. We found significant changes in the expression of 34 genes involved in inflammation processes. The detailed analysis of quantitative data showed that the Bcl6 gene, which plays a main role in the formation and development of the immune system, exhibited significant changes in its expression levels in response to injection of each of the peptides. Also, we observed expression changes for Bcl6 target and corepressor genes under the influence of Selank and its fragments. Our results showed that Selank and its fragments caused a number of alterations in the expression of genes involved in inflammation. The data obtained confirmed the participation of Selank in the processes of regulation of inflammation in the body. The complex biological effect of Selank may be partially determined by the systematic effect of this peptide on genomic expression.

The effect of selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which is a synthetic derivative of the endogenous tetrapeptide tuftsin (stable with respect to tissue peptidases), on the learning and memory processes and metabolism of serotonin (5-HT) have been experimentally studied on Wistar rats. The animals were trained with food reward in 30 trials per day. Selank (300 microg/kg) or saline were injected after the 10th trial. Elaboration of conditioned reflex with food reward was continued 30 min later. Retention was tested 24 h, 7 and 30 days after treatment. A single injection of selank activated the metabolism of 5-HT in the hypothalamus and caudal brain stem for 30 min to 2 h. It was established that selank induces an increase in memory trace stability during 30 days. These findings provide direct evidence that selank, when injected during consolidation phase, can enhance memory storage processes. Nootrope activity of the selank is probably caused by its obvious effect on the level of serotonin and its metabolite in the brain.

A synthetic derivative of the endogenous peptide tuftsin heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) possesses an anxiolytic and psychostimulant effect, and represents a working element of a new peptide drug having completed the third phase of the clinical testing as a selective anxiolytic. The neurobiochemical spectrum of selank action combines mechanisms which are characteristics of antidepressants and psychostimulants: activation of the brain monoaminergic systems, dopamine synthesis and turnover, and modulation of the tyrosine hydroxylase activity. The aim of this study was to investigate the effect of selank in a new model of inherited (genetically-based) symptoms of depression in behavior of inbred WAG/Rij rats in comparison with its effect on situation-provoked symptoms of depression in behavior of BALB/c mice. Outbred Wistar rats constituted control group. Selank in high doses (1000-2000 microg/kg), after repeated injection counteracted symptoms of depression in behavior of WAG/Rij rats (increased immobilization in the forced swimming test and decreased sucrose intake or preference (anhedonia)). Selank in low doses (100 and 300 microg/kg) after single injection reduced the duration of immobility of BALB/c mice in the forced swimming test, but did not exert significant effect after repeated injection or after injection in high doses (600 and 900 microg/kg). Selank did not affect the level of general locomotor activity and anxiety in WAG/Rij rats, and did not exert substantial effect on the behavior of control Wistar rats. The results demonstrate the presence of antidepressant component in the spectrum of neuropsychotrophyc activity of selank and indicate the higher reliability of a new experimental model of depression (the WAG/Rij rats) as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

The purpose of this article was to study the immunotropic effects of the new neurotrophic heptapeptide selank. The experiments in vitro revealed that the drug in concentration 10-7 M completely suppressed gene expression by peripheral blood IL-6 of patients with depression but not of the healthy controls. At the same time, the significant increase (p<0,05) of IL-6 concentration was observed in the cell culture of peripheral blood of patients in the presence of selank. The changes of the Th1/Th2 cytokine balance in vivo were found in the serum of patients with generalized anxiety disorder and neurasthenia who received Selank during 14 days. The dynamics of these changes had the significant inverse correlation dependence. The cytokine regulating effects revealed in the study suggest that selank can be used as a novel immunomodulator in patients with anxiety-asthenic disorders. Additionally, the adaptogenic properties of selank may be beneficial to its use in elderly people and people exposed to environmental stressors for the prevention of infectious diseases.

The actions of the synthetic heptapeptide preparation Selank on learning and memory processes in rats with initially low levels of learning ability were compared with those in normal rats, using a method based on acquisition of a conditioned active avoidance reflex, with repeated administration of peptide 15 min before the start of training sessions for four days. The effects of Selank (300 microg/kg) were compared with the effects of the nootrope piracetam (400 mg/kg). These experiments showed that Selank significantly activated the learning process in rats with initially poor learning ability, with effects apparent after first dose on training day 1. The effect progressively increased on repeated administration of Selank: the total number of correct solutions increased and the number of errors decreased (p < 0.05). The maximum optimizing activity of Selank on learning in normal rats was seen on day 3 of repeated administration and training, i.e., after formation of the initial consolidation phase. The dynamic features of the development of the activating action of Selank and piracetam were described. Comparison of the results obtained here with data on the anti-anxiety actions of Selank suggested potential for its use in optimizing mnestic functions in conditions of elevated emotional tension.