Semax and Selank: regulatory peptides from Russian neuroscience

Semax and Selank are two short synthetic peptides that emerged from Russian research on regulatory peptides, the small signalling molecules through which the body coordinates activity between cells and organs. Both are studied mainly for effects on the brain: Semax for cognition and recovery after stroke, Selank for anxiety. They are well known in Russian neuroscience and much less studied elsewhere. This review sets out what the published research shows, and the particular difficulties of assessing an evidence base produced largely within one country.

The regulatory-peptide approach

Many hormones and neuropeptides are large molecules whose different activities reside in different parts of the chain. One research strategy is to identify a short fragment that carries a desired activity, then modify it so that it survives longer in the body. Semax and Selank both follow this approach, and they share a design feature: a C-terminal proline–glycine–proline (Pro-Gly-Pro) extension added to a short active sequence.

Semax has the sequence Met-Glu-His-Phe-Pro-Gly-Pro. It is an analogue of a fragment of adrenocorticotropic hormone (ACTH 4–10). It is typically given by nasal application in the research literature^[1]. Its name in some studies, ACTH(4–7)PGP, describes this structure directly.

Selank has the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro. It is described by its developers as a heptapeptide with prolonged anxiety-reducing and nootropic effects^[2].

A notable feature of the literature is its concentration. The same researchers, including Nikolai Myasoedov, appear as co-authors across much of the work on both peptides, from synthesis to animal and clinical studies^[1][2][3].

Semax: proposed mechanisms

The most developed mechanistic hypothesis for Semax involves brain-derived neurotrophic factor (BDNF), a protein that supports the survival of neurons and the strengthening of connections between them. In rats, a single application of Semax increased BDNF protein in the hippocampus by up to 1.4-fold and phosphorylation of its receptor, TrkB, by 1.6-fold. Treated animals also performed a conditioned avoidance task better^[1]. A related study found specific, high-affinity binding sites for Semax in membranes from the rat basal forebrain, and a rise in BDNF in that region within three hours of intranasal application^[4].

A second line of research concerns stroke models. After temporary occlusion of a brain artery in rats, Semax altered the expression of 394 genes compared with saline. It suppressed genes related to inflammation and activated genes related to neurotransmission, broadly counteracting the changes caused by ischaemia^[5]. An earlier genome-wide study, after permanent arterial occlusion, found that Semax mainly enhanced the expression of immune-related genes and altered genes involved in the vascular system^[6].

These studies describe what happens in rat brain tissue after Semax treatment. They do not identify a single primary mechanism, and the gene-expression findings are broad descriptions rather than tests of which changes matter.

Selank: proposed mechanisms

Research on Selank has focused on the GABA system, the brain's main inhibitory network and the target of benzodiazepine anxiolytics. In binding studies using brain membranes, Selank acted as a positive allosteric modulator of GABA binding. Its interaction with benzodiazepines was not simply additive, and the authors concluded that their binding sites were probably different but might partly overlap^[2].

Gene-expression studies support a GABA-related action but also show its limits. In rat frontal cortex, Selank changed the expression of 45 of 84 neurotransmission-related genes one hour after administration, and the pattern correlated with changes produced by GABA itself^[7]. In a human neuroblastoma cell line, however, Selank had no direct effect on the expression of GABAergic system genes, although it altered the effects of the antipsychotic olanzapine^[8]. In a rat model of chronic mild stress, Selank reduced anxiety-like behaviour and enhanced the effect of diazepam^[9].

Human studies

Published human research exists for both peptides, almost entirely in Russian journals.

These studies are the core of the clinical evidence, and their limitations are significant:

• Design. The available abstracts do not describe randomisation or blinding. The 1997 stroke study compared 30 treated patients with a separate group of 80, a design open to selection bias^[10].
• Comparators. The Selank study compared it with another anxiolytic, medazepam, rather than a placebo, so it cannot show how much improvement would have occurred without active treatment^[3].
• Size. Participant numbers are small for the conditions studied.
• Accessibility. Full texts are in Russian, which limits scrutiny by the wider scientific community.

The 2018 stroke study illustrates how hard these results are to interpret. Patients were grouped both by whether they received Semax and by whether they began rehabilitation early or late. Higher plasma BDNF was associated with better Barthel index scores. Early rehabilitation was itself associated with higher BDNF and better motor recovery, and the relationship between BDNF and outcome depended on rehabilitation timing^[11]. With several interacting factors and no randomisation described, it is difficult to isolate the contribution of the peptide itself. Plasma BDNF is also a surrogate marker: a rise in the blood does not show what is happening in the injured brain.

Geographic context and regulatory status

Russian researchers describe Semax as having been used successfully in treating patients with severe impairment of cerebral blood circulation^[5]. Outside Russia, the picture is different. A 2020 report from Belgian official medicines control scientists described two seized preparations that turned out to contain Selank and Semax. It characterised them as research peptides that, to the authors' knowledge, had not completed any clinical trials, and noted that such peptides were available online as powders for injection and as nasal sprays^[12].

The two accounts reflect different standards of evidence and different regulatory settings. The sources reviewed for this article do not support any statement that Semax or Selank are approved medicines in the United Kingdom, the European Union or the United States, and readers should not infer such approval from their clinical use in Russia.

What would strengthen the evidence

• Randomised, placebo-controlled, double-blind trials with pre-registered outcomes, conducted by independent groups.
• Publication of full trial reports in international journals, with data available for scrutiny.
• Pharmacokinetic studies showing how much peptide reaches the brain after nasal application in people.
• Independent replication of the BDNF and GABA-modulation findings.

Summary

Semax and Selank are products of a coherent Russian research programme built on the idea of stabilised regulatory-peptide fragments. Animal and cellular studies propose plausible mechanisms: BDNF/TrkB signalling for Semax and modulation of GABA receptor binding for Selank. Human studies exist in stroke and anxiety, but they are small, mostly published in Russian, and do not describe the randomised, blinded designs needed for firm conclusions. International regulatory recognition is not established in the sources reviewed. The literature is best regarded as promising but unconfirmed outside the tradition that produced it.