Semax vs Selank: How Two Related Research Peptides Differ

Semax and Selank are synthetic heptapeptides that appear related to endogenous regulatory peptides and are studied for their potential to support signaling within the central nervous system. Semax is considered an analog of a fragment of adrenocorticotropic hormone (ACTH), whereas Selank is considered an analog of tuftsin, a short immunomodulatory peptide derived from immunoglobulin G.

Despite their different parent molecules, both peptides appear to share the same C-terminal stabilizing tail of Pro-Gly-Pro, which is why they are often discussed together in the scientific literature. This C-terminal attachment is also posited to improve access of the molecules to nerve cells through barriers. Indeed, both peptides are primarily researched regarding their potential on nerve cells and nerve cell signaling.

 

What Does Research Show About Semax vs Selank?

How Similar Are Semax and Selank in Structure?

Semax and Selank were both developed by modifying short endogenous regulatory peptides with the Pro-Gly-Pro tripeptide attachment at the C-terminus. According to a review by Kolomin et al., regulatory peptides are typically degraded very rapidly by proteases in biological media, which limits their research relevance. On the other hand, these modifications were reportedly intended to produce compounds with “a considerably longer half-life compared with that of [endogenous] molecules”, while retaining their ability to act on specific body systems.⁽¹⁾

Both peptides are relatively small and composed only of natural L-amino acids. More specifically, research by Kost et al. suggests that in Semax, Met-Glu-His-Phe corresponds to the ACTH 4-7 region, while in Selank, Thr-Lys-Pro-Arg corresponds to the full tuftsin sequence.⁽²⁾ Both peptides also share the same C-terminal Pro-Gly-Pro tripeptide. This tripeptide belongs to the glyproline family and is hypothesized to improve resistance to enzymatic degradation. Therefore, the two peptides appear to share a similar stabilizing strategy, while their N-terminal active regions are structurally unrelated.

Because the N-terminal regions differ, the peptides appear to also differ in their primary research focus. Notably, the research by Kolomin et al. describes Semax primarily in the context of neuroprotection, and Selank primarily in the context of stress-related signaling.⁽¹⁾ Furthermore, Slominsky et al. also conducted experiments that tested both peptides in the same research model and also suggested that Selank reportedly decreased the level of stress-related signaling while Semax apparently did not.⁽³⁾ Instead, Semax may support neurotrophic factors, as suggested by studies from Dolotov et al. and other researchers.⁽⁴⁾

How May the Two Peptides Interact With BDNF and Other Neurotrophic Factors?

Brain-derived neurotrophic factor (BDNF) is a protein that appears to support the survival, growth, and plasticity of mammalian nerve cells. It is considered to act mainly through the tropomyosin receptor kinase B (trkB), and the BDNF/trkB system is thought to play an important role in mammalian nerve cell survival and function.

Research suggests that both peptides may interact with the BDNF/trkB system, but Semax appears to be the more extensively studied of the two peptides in this regard. Specifically, research by Dolotov et al. suggests that a single exposure to Semax may have produced a maximal 1.4-fold increase in BDNF protein levels in the models involving hippocampal nerve cells.⁽⁴⁾ This was apparently accompanied by a 1.6-fold increase in trkB tyrosine phosphorylation, which may indicate increased receptor activation. At the gene expression level, the researchers reported an approximately 3-fold increase in exon III BDNF mRNA and an approximately 2-fold increase in trkB mRNA.

The Semax-exposed models also reportedly showed a distinct increase in the number of conditioned avoidance reactions, which is a measure of nerve cell function and capacity. Based on these findings, Dolotov et al. suggested that Semax may affect cognitive nerve functions “by modulating the expression and the activation of the hippocampal BDNF/trkB system”.⁽⁴⁾

Selank has also been investigated for possible interactions with BDNF, although the data appears more limited. A brief report by Inozemtseva et al. suggested that Selank may also regulate BDNF expression in hippocampal nerve cells.⁽⁵⁾ Later research by other investigators has cited this work when hypothesizing that Selank may modulate BDNF-related signaling.

What Does Research Suggest About Enkephalin Signaling?

Enkephalins are endogenous opioid peptides that may play a role in pain signaling, stress-response signaling, and more. They are rapidly broken down by several peptidases, commonly called enkephalin-degrading enzymes or enkephalinases. Studies suggest that Semax and Selank may hold the potential to mitigate these enzymes, which may prolong the presence of enkephalins and potentially support their signaling.

For example, research by Kost et al. suggests that both Semax and Selank may mitigate enkephalin-degrading enzymes from serum in a concentration-dependent manner.⁽²⁾ Semax apparently produced half-maximal mitigation (IC₅₀) at approximately 10 μM, while Selank achieved IC₅₀ at approximately 20 μM. Both peptides therefore appeared to be considerably more potent than the reference peptidase mitigator puromycin. The Semax and Selank peptides also reportedly exceeded the mitigatory activity of bacitracin and some other peptidase mitigators.

How May Semax and Selank Interact With Serotonin Signaling?

Serotonin (5-hydroxytryptamine) is a monoamine neurotransmitter, and the activity of serotonergic neurons is commonly estimated by measuring 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, as increased levels may reflect increased serotonin turnover. Research by Eremin et al. suggests that Semax may positively modulate the serotonergic system in the medium spiny neurons typically found in the striatum.⁽⁶⁾ The tissue content of 5-HIAA in the medium spiny neurons apparently increased by approximately 25% two hours after Semax exposure. Moreover, the extracellular level of 5-HIAA reportedly increased gradually up to 180% within one to four hours. The researchers interpreted these findings as data of the positive modulatory relevance of Semax on the striatal serotonergic system.

For Selank, the data regarding serotonin appears more indirect. For example, Volkova et al. noted that Selank had previously been suggested to modulate dopamine and serotonin receptors, and analyzed several serotonin receptor genes in frontal cortex neurons.⁽⁷⁾ For example, the expression of the Htr3a gene reportedly decreased to 0.52-fold one hour after Selank exposure, and increased to 1.66-fold after three hours.

How Do the Peptides Differ in Other Neurotransmitter Systems?

Beyond the shared areas of research, the two peptides appear to diverge in the neurotransmitter systems that have been most closely associated with them. Semax has been studied mainly in relation to dopamine, whereas Selank has been studied mainly in relation to gamma-aminobutyric acid (GABA).

In the aforementioned experiments by Eremin et al., Semax apparently supports the stimulus of other molecules that may increase dopamine release. Specifically, the findings suggest that Semax may not directly stimulate dopamine release, but may instead act as a modulator that enhances the responsiveness of the dopaminergic system to other stimuli. The researchers posit that the close functional and anatomical links between melanocortinergic and monoaminergic brain systems may help explain this effect, considering that Semax is derived from the melanocortin peptide ACTH.

On the other hand, Volkova et al. suggest that Selank may act as an allosteric modulator of GABA-A receptors.⁽⁷⁾ To test whether Selank and GABA may share a similar mechanism, the researchers analyzed the expression of 84 neurotransmission-related genes in the frontal cortex neurons one and three hours after exposure to either Selank or GABA. One hour after exposure, 45 genes reportedly changed their expression, 29 of them after Selank and 41 after GABA. The changes caused by the two compounds were apparently strongly correlated (r = 0.86). For example, both Selank and GABA appeared to reduce the expression of the GABA-A receptor subunit genes Gabre and Gabrq to approximately 0.05-fold, and both reduced the expression of GABA transporter genes such as Slc6a1 and Slc6a11.

Three hours after exposure, only 22 genes apparently showed altered expression, 17 after Selank and 9 after GABA, and the correlation between the two compounds became weakly negative (r = −0.39). At this time, Selank reportedly increased the expression of Gabre approximately 16.1-fold and Gabrq approximately 13.3-fold, while GABA did not appear to produce such changes.

Based on these findings, the researchers suggested that one of Selank’s possible molecular mechanisms may be associated with allosteric modulation of the operation of the GABAergic system.⁽⁷⁾ They further hypothesized that Selank may alter the affinity of GABA receptors rather than acting directly at the GABA binding site.

 

Frequently Asked Questions

What are Semax and Selank, and where do they come from?

Semax and Selank are synthetic heptapeptides that were developed from naturally occurring regulatory peptides. Semax is considered an analog of the ACTH 4-10 fragment, while Selank is considered an analog of tuftsin, an immunomodulatory peptide derived from immunoglobulin G. Both were designed to be more stable than their parent molecules.

How do Semax and Selank differ in structure?

Both peptides are seven amino acids long and share the same C-terminal Pro-Gly-Pro tripeptide, which is hypothesized to improve their resistance to enzymatic degradation. However, their N-terminal regions differ. Semax begins with Met-Glu-His-Phe, which corresponds to ACTH 4-7, while Selank begins with Thr-Lys-Pro-Arg, which corresponds to the tuftsin sequence.

Do Semax and Selank share a mechanism of action?

The two peptides may share some mechanisms. Both appear to mitigate enzymes that degrade enkephalins, and both have been suggested to support BDNF expression in the hippocampus. However, they also appear to differ. Semax has mainly been associated with modulation of dopaminergic and serotonergic signaling, while Selank has mainly been associated with possible allosteric modulation of the GABAergic system.

Have Semax and Selank been studied side by side?

Only a few experiments appear to have studied both peptides together. Kost et al. compared their ability to mitigate enkephalin-degrading enzymes in vitro, and Slominsky et al. compared their effects on behavior in the same model of dopaminergic damage. Most other studies have investigated each peptide separately, which makes direct comparisons difficult.

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

1. Kolomin, T., Shadrina, M., Slominsky, P., Limborska, S., & Myasoedov, N. (2013). A new generation of drugs: synthetic peptides based on natural regulatory peptides. Neuroscience and Medicine, 4(4), 223–252. https://doi.org/10.4236/nm.2013.44035
2. Kost, N. V., Sokolov, O. Y., Gabaeva, M. V., Grivennikov, I. A., Andreeva, L. A., Miasoedov, N. F., & Zozulia, A. A. (2001). Semax and selank inhibit the enkephalin-degrading enzymes from human serum. Bioorganicheskaia khimiia, 27(3), 180–183. https://doi.org/10.1023/a:1011373002885
3. Slominsky, P. A., Shadrina, M. I., Kolomin, T. A., Stavrovskaya, A. V., Filatova, E. V., Andreeva, L. A., Illarioshkin, S. N., & Myasoedov, N. F. (2017). Peptides semax and selank affect the behavior of rats with 6-OHDA induced PD-like parkinsonism. Doklady Biological Sciences, 474(1), 106–109. https://doi.org/10.1134/S0012496617030048
4. Dolotov, O. V., Karpenko, E. A., Inozemtseva, L. S., Seredenina, T. S., Levitskaya, N. G., Rozyczka, J., Dubynina, E. V., Novosadova, E. V., Andreeva, L. A., Alfeeva, L. Y., Kamensky, A. A., Grivennikov, I. A., Myasoedov, N. F., & Engele, J. (2006). Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus. Brain Research, 1117(1), 54–60. https://doi.org/10.1016/j.brainres.2006.07.108
5. Inozemtseva, L. S., Karpenko, E. A., Dolotov, O. V., Levitskaya, N. G., Kamensky, A. A., Andreeva, L. A., & Grivennikov, I. A. (2008). Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo. Doklady Biological Sciences, 421, 241–243. https://doi.org/10.1134/s0012496608040066
6. Eremin, K. O., Kudrin, V. S., Saransaari, P., Oja, S. S., Grivennikov, I. A., Myasoedov, N. F., & Rayevsky, K. S. (2005). Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents. Neurochemical Research, 30(12), 1493–1500. https://doi.org/10.1007/s11064-005-8826-8
7. Volkova, A., Shadrina, M., Kolomin, T., Andreeva, L., Limborska, S., Myasoedov, N., & Slominsky, P. (2016). Selank administration affects the expression of some genes involved in GABAergic neurotransmission. Frontiers in Pharmacology, 7, 31. https://doi.org/10.3389/fphar.2016.00031