Neuropeptides Research

Semax and Selank are synthetic peptides. In animal models they show cognition-modulating effects, anxiolytic-like effects, and neurotrophic signaling. Some literature also discusses other short peptides with neuromodulatory effects, such as DSIP, PE-22-28, VIP and N-Acetyl Semax. That literature groups them by their common "nootropic" properties.

The sections below discuss some of that literature. It is mostly a mix of molecular, animal, and limited human findings. Most of it comes from the Russian scientific community. These compounds are still being investigated for the effects described above. Nothing below is a statement on outcomes in people.

What These Peptides Share, and What They Do Not

By any available validated pharmacological classification, these peptides do not belong to one receptor family. They do not produce a single outcome either. Instead, the literature connects them to various neuromodulatory effects, sometimes with shared functions in learning and memory.

Animal studies report that they increase the expression of neurotrophins such as BDNF and NGF. Neurotrophins are proteins that support nerve cells. Those studies also describe changes to ion channels and to related signaling proteins involved in how nerve cells fire. So in animal models, these peptides show effects on inhibitory signaling between nerve cells. They also show effects on how the animals behave in tests of stress, depression, anxiety, or memory and learning.

What Semax, Selank, DSIP and PE-22-28 Are

Semax is commonly described as a heptapeptide derived from ACTH, meaning it is seven amino acids long. Its sequence is Met-Glu-His-Phe-Pro-Gly-Pro. Selank is a synthetic tuftsin analog, with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro. Russian research settings developed both peptides, and those same settings generated most of the human data.

The literature also discusses similar short peptides that show neuromodulatory effects. One is the delta sleep-inducing peptide, or DSIP. Another is PE-22-28, a seven amino acid peptide. It shows inhibition of TREK-1 channels, a type of potassium channel. PE-22-28 also shows antidepressant-like behavior in mice.

BDNF Findings in Rats and in Cultured Cells

In rats, a single intranasal application of Semax increased BDNF protein in the hippocampus.[1] That application also increased trkB tyrosine phosphorylation, and the mRNA levels of BDNF and trkB.[1] The same study reported improved performance in conditioned avoidance testing, a learning task.[1]

A peptide with a similar function is vasoactive intestinal peptide, or VIP. In primary cultures of mouse cortical neurons and astrocytes, grown in the laboratory, VIP strengthened the effect of glutamate on BDNF expression.[2]

What the Enkephalin and GABA Studies Showed

In human serum in vitro, meaning outside a living body, Semax and Selank inhibited the enzymes that break down enkephalins, in a dose-dependent manner.[3] The IC50, the concentration that cut enzyme activity in half, was 10 µM for Semax and 20 µM for Selank.[3] Both were more potent than puromycin or bacitracin in the same assay.[3]

Enkephalins are known natural anxiolytics, molecules the body makes that reduce anxiety. The authors suggest one mechanism by which the anxiolytic and cognitive effects of the peptides could be elicited: maintaining enkephalin levels. Human serum was used in this study, but this cannot be accounted as human clinical evidence. Establishing that would require a human clinical trial, in which different pharmacological parameters must be considered and evaluated.

A similar observation was reported in mice, but it was not consistent across the two strains studied.[4] BALB/c mice showed anxiolytic behavior together with an increased half-life of plasma leu-enkephalin, meaning it lasted longer in the blood.[4] The same study found no effect of Selank on behavior or enkephalinase activity in C57Bl/6 mice.[4]

In a separate in vivo study, meaning one in living animals, Selank altered the expression of genes involved in GABA signaling in the frontal cortex of rats.[5] The pattern of change resembled that produced by GABA itself.[5] That supports a plausible link to anxiolytic-like pharmacology.[5]

Animal Data Versus Human Data

This literature splits clearly in two: extensive animal and in vitro work, and a much smaller human literature.

For Semax, the strongest data are rodent studies. Those cover gene expression, learning-related behavior, and neuroprotection. Human reports are comparatively sparse, and they are often embedded in Russian-language clinical traditions.

For Selank, human studies exist. They include a comparative trial in 62 patients with generalized anxiety disorder and neurasthenia. In that trial, Selank produced anxiolytic effects broadly similar to medazepam.[6] Such studies are few, region-specific, and published in Russian. They have not been broadly replicated in large multinational programs.

DSIP is even less secure as a translational candidate. Its underlying biology is unresolved, and so is the original hypothesis that it acts as a sleep factor. Older animal and human observations of DSIP exist, but they have not settled either question.

Limitations

Various literature groups the short peptides discussed above as a single class. But those peptides differ substantially in sequence, origin, target biology, and mechanisms of action. What they mainly share is the limited length of the amino acid chain.

Each of these four peptides is most strongly associated with a different part of the published work:

• Semax, with BDNF and NGF signaling in preclinical work.
• Selank, with anxiolytic and GABA-linked studies.
• DSIP, with sleep and neuroendocrine uncertainty.
• PE-22-28, with TREK-1 and antidepressant-like behavior in animal models.

Another limitation is that many human reports are confined to a single geographic area. That leaves two important questions unresolved: whether the findings generalize, and whether independent groups can replicate them.

Two Semax derivatives illustrate the same limitation from a different direction. Researchers have characterized N-Acetyl Semax largely in vitro. They report that, compared with the parent peptide, it binds metals differently and behaves differently in oxidation and reduction reactions.

Adamax is an adamantane-modified Semax analog. It has almost no independent literature of its own, and the available preclinical evidence describes Semax rather than the derivative. In both cases the parent peptide's evidence base is doing most of the work. Effects should not be assumed to transfer to a modified sequence without direct study of that sequence.

Research Directions

The most useful next step in validating these peptides would be to separate their mechanisms more clearly and to reproduce published effects in more independent studies.

One example is the change Semax produces in the expression of the neurotrophic factors BDNF and NGF. Linking those changes to behavior in animal models and to findings in human tissues would strengthen the evidence base.

For Selank, two findings would be worth reproducing in both animals and human tissues. Those are the change in GABA-related gene expression and the inhibition of enkephalin degradation. Doing so would help determine whether there are species-specific effects on behavior.

For DSIP, PE-22-28, VIP, N-Acetyl Semax and Adamax, the field would benefit from conclusive data on how each peptide interacts with receptors. It would also benefit from standardized assays that give reproducible activity data. Pairing biochemical effects with independent in vivo studies would help validate their functions across species.

Conclusion

Semax and Selank are neuromodulatory peptides. In preclinical models they have shown effects on gene expression, on neurotrophic signaling, and on inhibitory signaling between nerve cells. In those same preclinical models they have shown effects on how animals behave in tests related to anxiolytic and cognitive properties. The evidence has yet to be reproduced consistently across species.

Semax is most strongly associated with preclinical BDNF and NGF studies. Selank is most strongly associated with anxiolytic findings, with GABA and enkephalin-linked findings, and with a limited human literature. DSIP, PE-22-28, VIP, N-Acetyl Semax and Adamax each occupy more specific or less settled niches within the same research ecosystem.

References

1. 1

   Dolotov OV, Karpenko EA, Inozemtseva LS, Seredenina TS, Levitskaya NG, Rozyczka J, et al. Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Res. 2006;1117(1):54-60. [PMID 16996037](https://pubmed.ncbi.nlm.nih.gov/16996037/)
2. 2

   Pellegri G, Magistretti PJ, Martin JL. VIP and PACAP potentiate the action of glutamate on BDNF expression in mouse cortical neurones. Eur J Neurosci. 1998;10(1):272-280. [PMID 9753136](https://pubmed.ncbi.nlm.nih.gov/9753136/)
3. 3

   Kost NV, Sokolov OY, Gabaeva MV, Grivennikov IA, Andreeva LA, Myasoedov NF, Zozulya AA. Semax and Selank inhibit the enkephalin-degrading enzymes of human serum. Russ J Bioorg Chem. 2001;27(3):156-159. [PMID 11443939](https://pubmed.ncbi.nlm.nih.gov/11443939/)
4. 4

   Sokolov OY, Meshavkin VK, Kost NV, Zozulya AA. Effects of Selank on behavioral reactions and activities of plasma enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions. Bull Exp Biol Med. 2002;133(2):133-135. [PMID 12432865](https://pubmed.ncbi.nlm.nih.gov/12432865/)
5. 5

   Volkova A, Shadrina M, Kolomin T, Andreeva L, Limborska S, Myasoedov N, Slominsky P. Selank administration affects the expression of some genes involved in GABAergic neurotransmission. Front Pharmacol. 2016;7:31. [PMID 26924987](https://pubmed.ncbi.nlm.nih.gov/26924987/)
6. 6

   Zozulya AA, Neznamov GG, Siuniakov TS, Kost NV, Gabaeva MV, Sokolov OY, et al. Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia. Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(4):38-48. [PMID 18454096](https://pubmed.ncbi.nlm.nih.gov/18454096/)