Semax and Selank: the Russian heptapeptides in neuroscience research

Two peptides with a shared design

Semax and Selank were developed at the Institute of Molecular Genetics of the Russian Academy of Sciences in Moscow. Each is a heptapeptide, a chain of seven amino acids, built from a short, biologically active natural fragment followed by the tripeptide Pro-Gly-Pro. That tail makes the peptides much more resistant to enzymes that would otherwise break them down within minutes, which is why both have been studied by the intranasal route in animals.

Both are registered for medical use in Russia, but neither is approved in the UK, the US or the EU, and the published research comes largely from Russian groups.

Semax: an ACTH fragment without hormonal activity

Semax has the sequence Met-Glu-His-Phe-Pro-Gly-Pro. Its first four residues come from adrenocorticotropic hormone (ACTH), the pituitary hormone that drives cortisol production, but Semax is designed so that it keeps the brain-related activity of this region without stimulating the adrenal glands. Dolotov and colleagues describe it as an analogue of the ACTH(4-10) fragment with marked effects on learning and nerve-cell protection in animal studies.

Semax and BDNF

The best-characterised mechanism for Semax involves brain-derived neurotrophic factor (BDNF), a protein that supports the survival and plasticity of nerve cells, and its receptor trkB. Dolotov and colleagues found that a single intranasal application of Semax in rats raised BDNF protein in the hippocampus up to 1.4-fold and trkB phosphorylation, a sign of receptor activation, 1.6-fold. Messenger RNA levels rose three-fold for BDNF exon III and two-fold for trkB. Treated rats also made more conditioned avoidance responses in a learning task. The authors suggest that Semax affects cognitive function by modulating the BDNF/trkB system in the hippocampus.

Selank: a tuftsin analogue

Selank has the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro. Its first four residues are tuftsin, a natural immunomodulatory peptide derived from immunoglobulin G. Selank is studied mainly for anxiety-related behaviour in animals, and Russian clinical studies compared its spectrum of effects with classic benzodiazepines such as diazepam and phenazepam.

Selank and GABA-related genes

To test whether Selank shares a mechanism with benzodiazepines, Volkova and colleagues measured the expression of 84 genes involved in neurotransmission in the frontal cortex of rats, one and three hours after Selank or GABA. Selank changed the expression of 45 genes after one hour and 22 after three hours, and the changes caused by Selank correlated with those caused by GABA. The authors propose that one of Selank's mechanisms is allosteric modulation of the GABAergic system, the same broad system that benzodiazepines act on.

Selank also appears to influence immune signalling, which fits its tuftsin origin. Kolomin and colleagues measured 84 inflammation-related genes in mouse spleen after a single administration of Selank or two of its fragments and found significant changes in 34 of them, including the immune regulator Bcl6 and its target genes.

How they compare

Because their proposed mechanisms differ, some research designs use the two together; we offer a Semax + Selank blend for that purpose.

• Origin: Semax is built on an ACTH fragment; Selank on tuftsin.
• Main research themes: Semax in learning, memory and nerve-cell protection; Selank in anxiety-related behaviour and immune signalling.
• Proposed mechanisms: Semax through BDNF and trkB; Selank through GABAergic modulation and immune-related gene expression.
• Shared design: both end in Pro-Gly-Pro for stability and are studied intranasally in animals.

Reading the evidence

The studies above are careful molecular work, but they are short-term experiments in rodents, and most of the research on both peptides comes from a small number of groups in Russia. Gene-expression changes show what a peptide does to cells at a given moment; they do not by themselves establish longer-term effects. Independent replication outside Russia remains limited.

Pro-Gly-Pro and peptide stability

Short natural peptides such as ACTH fragments and tuftsin are broken down within minutes by peptidases in blood and tissue. The Pro-Gly-Pro tail added to both Semax and Selank makes the chains much harder for these enzymes to cut, because proline-rich sequences resist many common peptidases. Pro-Gly-Pro is also of interest in its own right as a naturally occurring collagen-derived peptide, and fragments of both heptapeptides are studied alongside the full chains. Kolomin and colleagues, for example, tested two Selank fragments next to the full peptide and found that they also changed the expression of immune genes such as Bcl6.

Key terms

• BDNF: brain-derived neurotrophic factor, a protein that supports the survival and plasticity of nerve cells.
• trkB: the receptor for BDNF; its phosphorylation shows that it has been activated.
• GABA: the main inhibitory neurotransmitter in the brain.
• Allosteric modulation: changing a receptor's response by binding at a site other than the main one.
• Tuftsin: a natural four-amino-acid immunomodulatory peptide (Thr-Lys-Pro-Arg).
• ACTH: adrenocorticotropic hormone, the pituitary hormone that drives cortisol release.

Designing studies

The gene-expression studies above found many changes within one to three hours, so timing matters: include early time points as well as later ones. Comparing the peptide with a reference compound, as Volkova and colleagues did with GABA, helps place its effects. For intranasal work in animals, keep the volume and the solvent the same across groups.

In summary

Semax and Selank show how a short natural fragment plus a stabilising tail can create a research peptide with a clear molecular footprint: BDNF signalling for Semax, and GABA-related and immune-related gene expression for Selank. Broader, independent studies are the main gap in the evidence for both.

Notes for laboratory work

Semax contains methionine, which oxidises easily in the presence of oxygen, light and metal ions, as Li, Schöneich and Borchardt describe. Keep the lyophilized powder sealed, frozen and dark, and prepare solutions shortly before use; Selank, which has no methionine or cysteine, is somewhat less sensitive. Both are small, water-soluble peptides. For intranasal administration in animal models, a ready-made solution can save preparation time: our Semax nasal spray is supplied at a declared 0.1% or 1%. See storing research peptides for general storage.

Frequently asked questions