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Selank: An emergent drug-free anxiety therapy w unique nootropic boost & anti-viral defense

Selank Peptide Overview

Selank is a somewhat mysterious peptide whose mechanism of action is not yet fully elucidated, despite the ample evidence collected so far that supports its unique clinical and preclinical efficacy. The benefits of Selank can be divided into the following categories:

  1. Reinforcement of the body’s protective opioid system [1]
  2. Therapy of generalized anxiety and neurasthenia (ie. abnormal weakness) [2], [3]
  3. Enhancement of learning and memory [4], [5]
  4. Strengthens antiviral immune function [6]
  5. Protects against alcohol-induced memory impairment [7]
  6. Improves symptoms associated with alcohol withdrawal [8]

Natural body-produced opioid system augmentation

One way in which Selank works is by promoting the stability of a group of natural molecules called enkephalins [1], which are our body’s natural opioid peptide pain-relievers (and are similar in function to endorphins [9]). Psychological stress is a state of mental or emotional strain or tension that results from adverse or demanding circumstances. Chronic stress is well known to induce anxiety disorders and major depression; it is also considered a risk factor for Alzheimer’s disease. Stress resilience is a positive outcome that is associated with preserved cognition and healthy aging.

Resilience presents psychological and biological characteristics intrinsic to an individual conferring protection against the development of psychopathologies in the face of adversity. How can we promote or improve resilience to chronic stress? Numerous studies have proposed mechanisms that could trigger this desirable process.

The roles of enkephalin transmission in the control of pain, physiological functions, like respiration, and affective disorders have been studied for more than 30 years. Incredibly, Selank is one of the first peptides shown to promote the stability of your body’s own natural enkephalin opioid system components, without introducing new opioids into your body (ie. morphine or its derivatives).

Therapy of generalized anxiety disorders & abnormal physical weakness (ie. neurasthenia)

In one study, a total of sixty-two patients with generalized anxiety disorder (GAD) and abnormal physical weakness were studied. The effect of Selank was compared to that of medazepam (a long-acting benzodiazepine used for acute anxiety). Patients’ mental and physical states were assessed with various psychometric scales, and enkephalin activity in the blood serum was measured as well.

The anti-anxiety effects of both drugs were similar but Selank had also anti-fatigue and psychostimulant effects. This clinical study revealed that patients with generalized anxiety and neurasthenia had the decreased level of enkephaIin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with Selank mostly in patients with GAD.

Selank is a synthetic version of a natural protein called tuftsin, which is an immunomodulatory peptide produced primarily in spleen. Selank is comprised of a small fraction of tuftsin, to which three natural amino-acids (Pro-Gly-Pro) are attached to improve overall peptide stability. This heptapeptide improves learning and memorization and causes antidepressant and anxiolytic effect.

It is possible to use Selank to optimize cognitive functions and as a potential new fast-acting and easy-dosed drug. Therefore, it was proposed to study such properties of the heptapeptide as its influence on anxiety-fear and body weight under a long-term treatment regimen. The experiment was performed on two dozen Wistar rats with the use of Rodina’s method.

There were three experimental groups of animals with high initial emotional reactivity: passive control group, active control group (receiving distilled water) and group treated with Selank at the dose of 0.3 mg/kg. The rats received doses every day. The experiments were conducted 15 min after the administration of the drug, one and two days after initial testing day, then 1, 2, 3 and 4 weeks after that. 

Selank reduced the anxiety-phobic states significantly starting from the second day of drug application. Moreover, the observed effects persisted throughout four weeks of the experiment, which confirmed effective long-term anxiolytic properties of the heptapeptide. In contrast to conventional anti-anxiety pharmaceuticals that cause drowsiness and weight gain, Selank did not cause any changes in wakefulness indicators or body mass. 

In another study of 60 patients with generalized anxiety, the efficacy and tolerability of Selank in comparison with phenazepam, a typical anti-anxiety medication. Pronounced anxiolytic and mild nootropic effects of Selank were demonstrated in this patient population. Incredibly, the anti-anxiety effect lasted for a week after last receiving the peptide. Selank also had a positive impact on the quality of life of the patients in subjective measures. The data obtained in the study extend therapeutic possibilities in the treatment of anxiety disorders by suggesting that peptides may be superior to standard of care anti-anxiety medications [3].

The largest study to date of Selank as a therapy for anxiety came from a 2015 clinical trial with 70 patients, in order to compare the efficacy and tolerability of monotherapy with phenazepam versus complex treatment with the Selank plus phenazepam in patients with anxiety disorders of all subtypes. A positive effect of phenazepam was achieved earlier in the optimization of treatment with Selank, using the Hamilton Depression Rating Scale. However, the combined treatment decreased the level of undesirable side-effects of phenazepam (attention and memory impairment, asthenia, sedation, increase in sleep duration, sexual disturbances, emotional indifference) during the course of treatment and after the phenazepam was withdrawn. 

Taken together, the therapeutic efficacy and reduction of side-effects had a positive impact on the quality-of-life of the patients treated with Selank as add-on to phenazepam therapy. The clinical trial physicians concluded that the results extend therapeutic possibilities of treatment of anxiety-spectrum disorders with the combination of benzodiazepine anti-anxiety medication plus Selank.

Drug-free antidepressant

Since Selank was shown to possesses an anxiolytic and psychostimulant effect and represents a working element of a new peptide drug which has completed the third phase of the clinical testing as a selective anti-anxiety medication, the next question to address was potential antidepressant activity. 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. 

It turns out that most patients who suffer from depressive symptoms do not reach minimum diagnostic criteria (number, severity, or duration of symptoms are insufficient) of major depression and are diagnosed as having minor or “sub-syndromal” or sub-threshold depression. For sub-threshold depression, different definitions exist, based on the number of depressive symptoms, duration of symptoms, exclusion criteria, and associated functional impairments. Below threshold symptomatic depression was defined as “any two or more simultaneous symptoms of depression, present for most or all of the time, at least two weeks in duration, associated with evidence of social dysfunction, occurring in individuals who do not meet criteria for diagnosis of major depression and/or dysthymia.”

Minor/subthreshold depression is associated with functional impairment, reduced quality of life, and the risk of developing into major depression. Therefore, it should be treated. Watchful waiting should be an option only for patients who, despite adequate information, are not interested in any kind of treatment. Psychotherapy has been found to be effective, but due to high cost of participation or reluctance to accept psychological “expert” opinion, may individuals do not find benefit from talk therapies. Studies on the efficacy of antidepressants in the treatment of minor depression have found clinically relevant benefits over placebo, particularly the newer, better-controlled trials.

One major advantage of antidepressants over psychotherapy is their immediate availability and the short period required to evaluate efficacy. However, conventional antidepressants like SSRI’s and SNRI’s often come with side effects that limit their overall usefulness to patients, especially for patients with minor mood disorders that nonetheless interfere with full enjoyment of their lives. 

Aside from the severity of depression, the patient’s attitude towards psychotherapy or antidepressant treatment is of major relevance and should be explored. For this reason, newer drug-free peptide therapies like Selank which does not possess documented side effects and are cheaper than psychotherapy have the potential to increase patient compliance. This is one of the main reasons that Selank may be poised to become a major player in emergent drug-free peptide therapies of minor mood disorders.

Additional preclinical evidence for antidepressant effect

A preclinical study was undertaken to investigate the effect of Selank in a new innovative model of inherited (ie. genetically based) symptoms of depression in behavior of WAG/Rij rats, and also in comparison with its effect on situation-provoked symptoms of depression in conventional BALB/c mice. Wistar rats constituted control group. Selank in moderate doses 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 dosing reduced the duration of immobility of BALB/c mice in the forced swimming test, but it 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 it did not exert substantial effect on the behavior of control Wistar rats.

These results demonstrate the presence of antidepressant component in the spectrum of psychotropic activity of Selank and indicate the higher reliability of a new experimental model of depression in rats as compared to the standard forced swimming test for the determination of antidepressant activity of a pharmacological drug.

Enhancement of learning & memory

In a 2008 study of monkeys, Selank was studied for its ability to compensate for disturbed learning functions [4].These results indicated that an intranasal administration of Selank produced long-term changes of the monkeys’ learning behavior that was disturbed during neurosis: elimination of fear and aggression and increasing orientational-explorative activity as well as facilitation of handling reactions and communication. 

It has been shown that unlike the earlier studied neurohormones (thyroliberin and ACTH4-10), Selank beneficial effects do not depend on the type of neurotic disturbances and produces a long-term compensatory character. Comparison of the data obtained on monkeys with results of similar studies on the more low-organized mammals (rodents) allow suggesting that the new peptide preparation Selank is a promising agent for correction of various learning disturbances.

Selank was also investigated for its role on learning and memory processes in rats—both in animals with low learning ability and 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 nootropic 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.

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 learning functions in conditions of elevated emotional tension.

Strengthens antiviral immune function

Widening of the spectrum of antiviral compounds remains an urgent task, especially in the age of COVID-19. Until now, viral diseases including influenza, herpes, and cytomegaloviral (CMV), are widespread and poorly controlled infections. Therefore, development of new safe antiviral therapeutics is very important. Peptides constitute one of the most promising classes of physiologically active substances and understudied candidates for creation of new therapeuticsNumerous emergent peptide-based antiviral therapeutics have demonstrated virtually no negative side effects because they are endogenous substances and do not accumulate in tissues long-term. Thus, development of new antiviral drugs on the basis of peptide chemistry is an urgent and socially important task.

Previous research has shown that Selank possesses antiviral activity, via induction of secretion of interferons which can protect cells from the cytopathological effects of certain viruses. Specifically, Selank has exhibited antiviral activity against the influenza virus strain H3N2, experimental herpes infection induced by HSV2, and experimental viral human encephalomyocarditis [6]. More recently, this was recapitulated in vivo using a mouse model system in which Selank protected mice against influenza virus A strain H5N1, influenza virus B, herpes simplex types 1 and 2, and mouse encephalomyocarditis virus [6]. Thus, Selank offers a new avenue of antiviral therapy research going forward.

Protects against alcohol-induced memory impairment & withdrawal symptoms

Due to the well-established anti-anxiety function of Selank, scientists wanted to determine whether Selank could protect against alcohol withdrawal symptoms (which are highly influenced by general anxiety state). In one study, scientists studied the effects of Selank on the development of anxiety symptoms of acute 48-hour alcohol use preclinically using a 10% ethanol beverage for 24 weeks [8]. In alcohol-preferring animals who were allowed free choice between 10% ethanol and water, a single dose of Selank eliminated anxiety induced by ethanol withdrawal as determined by the elevated plus maze test and social interaction tests. Furthermore, Selank prevented pain response to footpad irritation in animals, yet without affecting ethanol consumption.

This remarkable effect was entirely unexpected and has spurred ongoing investigation into its origins, and additional studies investigating the positive effects of the Selank on age-related memory disturbances associated with chronic alcohol intoxication. This addition study confirmed the involvement of the neurotrophin-based mechanism related to BDNF production induced by Selank which led to a reduction in memory impairment brought on by chronic alcohol intake [7].

This information is provided for educational purposes only. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

References

  1. A. A. Zozulya et al., “The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity,” Bull. Exp. Biol. Med., 2001.
  2. A. A. Zozulya et al., “Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia,” Zhurnal Nevrol. i Psihiatr. Im. S.S. Korsakova, 2008.
  3. V. E. Medvedev et al., “A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders,” Zhurnal Nevrol. i Psihiatr. Im. S.S. Korsakova, 2014.
  4. T. N. Sollertinskaya, M. V. Shorokhov, M. M. Kozlovskaya, I. I. Kozlovskii, and K. V. Sudakov, “Compensatory and antiamnestic effects of heptapeptide Selank in monkeys,” J. Evol. Biochem. Physiol., 2008.
  5. I. I. Kozlovskii and N. D. Danchev, “The optimizing action of the synthetic peptide selank on a conditioned active avoidance reflex in rats,” Neurosci. Behav. Physiol., 2003.
  6. L. A. Andreeva et al., “Antiviral properties of structural fragments of the peptide Selank,” Dokl. Biol. Sci., 2010.
  7. L. G. Kolik, A. V. Nadorova, T. A. Antipova, S. V. Kruglov, V. S. Kudrin, and A. D. Durnev, “Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content in the Hippocampus and Prefrontal Cortex in Rats,” Bull. Exp. Biol. Med., 2019.
  8. L. G. Kolik, A. V. Nadorova, and M. M. Kozlovskaya, “Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation,” Bull. Exp. Biol. Med., 2014.
  9. M. S. Henry, L. Gendron, M. E. Tremblay, and G. Drolet, “Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience,” Neural Plasticity. 2017.

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