N-Acetyl Selank is an acetylated form of the heptapeptide Selank. Selank is a synthetic analog of the natural tetrapeptide tuftsin (threonine – lysine – proline – arginine). The sequence of N-Acetyl Selank is acetyl – threonine – lysine – proline – arginine – proline – glycine – proline. Adding proline – glycine – proline at the C-terminus and the acetylation at the N-terminus is intended to improve its stability compared to tuftsin. Tuftsin is found in the blood of various mammals as it is normally located in the Fc-domain of the heavy chain of immunoglobulin G (residues 289-292). As such, tuftsin is hypothesized to have immunomodulatory properties.

N-acetyl Selank peptide may potentially influence neurotransmitters, central nervous system signaling, and neuroplasticity. More specifically, the potential of N-acetyl Selank lies in higher cognitive functioning, serotonin signaling, and brain-derived neurotrophic factor (BDNF) expression. Studies on N-acetyl Selank are lacking, but data from Selank’s research may be used as a reference.

N-Acetyl Selank and Higher Cognitive Functions

One murine trial involving trained Winstar rats investigated the potential of the non-acetylated version of N-Acetyl Selank for influencing learning, memory, and serotonin levels.^[1] According to the research, N-Acetyl Selank may upregulate serotonin metabolism in the hypothalamus and caudal brain stem for 30 minutes to 2 hours. Additionally, N-Acetyl Selank may have a positive influence on memory trace stability for a period of 30 days. These findings suggest that N-Acetyl Selank may have favorable potential on memory storage processes during the consolidation phase of memory formation. The researchers also speculated that the potential of N-Acetyl Selank for improving higher cognitive functions may be attributed to its possible influence on serotonin levels and metabolites in the brain.

Furthermore, one clinical study by Medvedev et al. (2014) noted the potential of the non-acetylated version of N-Acetyl Selank when used in isolations.^[2] The researchers commented on the apparent improvement in the results of several scales for mood, such as HDRS, CGI, Spilberger, and SF-36. They also share that the “effect lasted for a week after last receiving the peptide.”

In another publication from 2015, the same researchers also suggest that N-Acetyl Selank may positively influence chemically induced asthenia, attention, and memory impairment.^[3] The researchers hypothesized that this might be due to the potential action of N-Acetyl Selank on higher cognitive functions.

N-Acetyl Selank and Enkephalins

Enkephalins are considered to be the natural ligands to the opioid receptors in the nervous system and play a role in mood and nociception. One clinical study suggested that low levels of tau(1/2) leu-enkephalin, a specific parameter related to enkephalin activity in serum, may have anxiogenic potential.^[4] Yet, the non-acetylated version of N-Acetyl Selank may potentially increase tau(1/2) leu-enkephalin levels. The researchers also noted that the peptide had an apparently favorable potential on psychometric scales such as Hamilton, Zung, and CGI, likely due to its possible interaction with the enkephalin signaling in the central nervous system.

Another clinical trial posited a decreased half-life of enkephalins and reduced total enkephalinase activity might have anxiogenic activity.^[5] The non-acetylated version of N-Acetyl Selank was suggested to block the enzymatic hydrolysis of plasma enkephalins by inhibiting enkephalinase activity. The researchers commented that the peptide “inhibited enzymatic hydrolysis of plasma enkephalin […]. Selank was more potent than peptidase inhibitors bacitracin and puromycin in inhibiting enkephalinases.”

N-Acetyl Selank and Serotonin Signaling

Semenova et al. (2009) investigated the potential of the non-acetylated version of N-Acetyl Selank on influencing serotonin (5-HT) signaling in the brains of Wistar rats.^[6] The rats were exposed to a 5-HT synthesis inhibitor called p-chlorophenyl alanine (PCPA) four days before the experiment. There were a total of 87 mature rats included in the study. The scientists commented that the non-acetylated version of N-Acetyl Selank may increase 5-HT metabolism in the brain stem despite exposure to PCPA. This suggests that the peptide N-Acetyl Selank may potentially improve disturbances caused by a decrease in 5-HT metabolism.

N-Acetyl Selank and Neurotrophic Growth Factors

Brain-derived neurotrophic factor (BDNF) is a neurotrophic growth factor studied for its potential to support neuroplasticity and synaptogenesis, neural remodeling, neurogenesis, nerve cell growth, survival, and adaptation.^{[7] [8]} Scientists also note, “The neurotrophic factor BDNF is an important regulator for the development of brain circuits, for synaptic and neuronal network plasticity, as well as for neuroregeneration and neuroprotection.”^[9]

Several researchers have investigated the potential of the non-acetylated version of N-Acetyl Selank on BDNF expression in the rat hippocampus.^[10] More specifically, the researchers measured the expression of BDNF mRNA and protein levels, as this neurotrophic growth factor is a potentially important regulator of memory formation.

The reported findings suggest that N-Acetyl Selank may stimulate the expression of BDNF in the hippocampus, indicating a potential role in regulating hippocampal function. This is based on comments that the non-acetylated version of N-Acetyl Selank appeared to upregulate BDNF mRNA expression in the rat hippocampus. Similarly, the protein level of BDNF in the hippocampus also appeared to increase after introducing the peptide. 

Conclusion

In conclusion, N-Acetyl Selank may exhibit the potential to impact neurotransmitters, central nervous system signaling, and neuroplasticity. Studies suggest that N-Acetyl Selank may positively influence higher cognitive functions, including memory and learning processes, potentially through action on serotonin levels and BDNF expression. Furthermore, its proposed interaction with enkephalin signaling in the central nervous system may contribute to its vast research potential.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Semenova TP, Kozlovskiĭ II, Zakharova NM, Kozlovskaia MM. [Experimental optimization of learning and memory processes by selank]. Eksp Klin Farmakol. 2010 Aug;73(8):2-5. Russian. PMID: 20919548.
2. Medvedev VE, Tereshchenko ON, Israelian AIu, Chobanu IK, Kost NV, Sokolov OIu, Miasoedov NF. [A comparison of the anxiolytic effect and tolerability of selank and phenazepam in the treatment of anxiety disorders]. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(7):17-22. Russian. PMID: 25176261.
3. Medvedev VE, Tereshchenko ON, Kost NV, Ter-Israelyan AY, Gushanskaya EV, Chobanu IK, Sokolov OY, Myasoedov NF. [Optimization of the treatment of anxiety disorders with selank]. Zh Nevrol Psikhiatr Im S S Korsakova. 2015;115(6):33-40. Russian. doi: 10.17116/jnevro20151156133-40. PMID: 26356395.
4. Zozulia AA, Neznamov GG, Siuniakov TS, Kost NV, Gabaeva MV, Sokolov OIu, Serebriakova EV, Siranchieva OA, Andriushenko AV, Telesheva ES, Siuniakov SA, Smulevich AB, Miasoedov NF, Seredenin SB. [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. Russian. PMID: 18454096.
5. Zozulya AA, Kost NV, Yu Sokolov O, Gabaeva MV, Grivennikov IA, Andreeva LN, Zolotarev YA, Ivanov SV, Andryushchenko AV, Myasoedov NF, Smulevich AB. The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity. Bull Exp Biol Med. 2001 Apr;131(4):315-7. doi: 10.1023/a:1017979514274. PMID: 11550013.
6. Semenova TP, kozlovskiĭ II, Zakharova NM, Kozlovskaia MM. [Comparison of the effects of selank and tuftsin on the metabolism of serotonin in the brain of rats pretreated with PCPA]. Eksp Klin Farmakol. 2009 Jul-Aug;72(4):6-8. Russian. PMID: 19803361.
7. Deister C, Schmidt CE. Optimizing neurotrophic factor combinations for neurite outgrowth. J Neural Eng. 2006 Jun;3(2):172-9. doi: 10.1088/1741-2560/3/2/011. Epub 2006 May 16. PMID: 16705273.
8. Lu B, Figurov A. Role of neurotrophins in synapse development and plasticity. Rev Neurosci. 1997 Jan-Mar;8(1):1-12. doi: 10.1515/revneuro.1997.8.1.1. PMID: 9402641.
9. Brigadski, T., & Leßmann, V. (2020). The physiology of regulated BDNF release. Cell and tissue research, 382(1), 15–45. https://doi.org/10.1007/s00441-020-03253-2
10. Inozemtseva LS, Karpenko EA, Dolotov OV, Levitskaya NG, Kamensky AA, Andreeva LA, Grivennikov IA. Intranasal administration of the peptide Selank regulates BDNF expression in the rat hippocampus in vivo. Dokl Biol Sci. 2008 Jul-Aug;421:241-3. doi: 10.1134/s0012496608040066. PMID: 18841804

At the molecular level, Acetyl Hexapeptide-3 is hypothesized to act as a competitive inhibitor of SNAP25 (synaptosome-associated protein 25), a component of the SNARE (soluble NSF attachment protein receptor) complex. The protein is named SNAP25 due to its size of 25 kDa. The SNARE complex is considered to play a crucial role in synaptic vesicle Ca(2+)-dependent exocytosis, which involves the release of neurotransmitters such as acetylcholine. Acetylcholine is a neurotransmitter linked to muscle contractions.

By possibly inhibiting acetylcholine exocytosis, Acetyl Hexapeptide-3 may interfere with the function of neuromuscular synapses and prevent the contraction of muscle cells. This mechanism appears similar to the way bacterial toxins, such as the toxin producers by Clostridium botulinum – (BoNTs) – are considered to interact and inhibit neuromuscular synapses. However, Acetyl Hexapeptide-3 may have a potential advantage in terms of permeation through the epidermis due to the attachment of acetyl moiety at the N-terminus of the peptide.^[1]

Acetyl Hexapeptide-3 may also interact with other aspects of the function of the nervous system, such as potentially inhibiting nociception. The peptide may also potentially impact collagen production and/or degradation.

Acetyl Hexapeptide-3 and Dermal Topography

Clinical studies suggest that Acetyl Hexapeptide-3 may improve the topography of dermal structures, such as wrinkle depth reduction, by as much as 30% – 48.9%.^{[2] [3]} The scientists posit that the peptide acts by inhibiting the release of neurotransmitters such as acetylcholine in the neuromuscular synapses. They also share that “inhibition of neurotransmitter release was due to the interference of the hexapeptide with the formation and/or stability of the protein complex that is required to drive Ca(2+)-dependent exocytosis, namely the vesicular fusion (known as SNARE) complex.“^[2]

Researchers also commented that the main potential mechanisms of Acetyl Hexapeptide-3, namely the competitive inhibition of SNAP-25, may be due to sharing a similar amino acid sequence pattern from the N-terminal end of synaptosomal-associated protein-25.^[4] This appears to prevent the formation of the ternary soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complex and interfere with neurotransmitter release, similar to BoNTs. In accordance with the potential action of Acetyl Hexapeptide-3, the contraction of the intrinsic muscles appears to be inhibited.

Acetyl Hexapeptide-3 and Collagen Synthesis

Some studies have investigated the potential Acetyl Hexapeptide-3 influence on collagen synthesis, a vital component of the extracellular matrix considered responsible for the structure and elasticity of connective tissues. The peptide has been suggested to interact with collagen production, potentially affecting the histological structure of dermal tissue.

Murine trials that lasted for at least 6 weeks suggest that the peptide may lead to an apparent increase in type I collagen fibers and a decrease in type III collagen fibers.^[5] The scientists used hematoxylin-eosin (HE) and picrosirius-polarization (PSP) stains to assess these histological changes in the dermal tissues. Furthermore, the amount of type I and type III collagen fibers were also semi-quantitatively compared using the software Image-ProPlus.

Due to its potential for reducing type III collagen fibers, Acetyl Hexapeptide-3 may also help reduce scarring during and after tissue regeneration. Some researchers comment that the peptide appears to increase the elasticity of scarred tissue “from 33,5% to 40,5% (…) in left lateral-medial area of the neck and malar area; from 24% to 31,5% (…) in right lateral- medial area of the neck and malar area; and from 25,5% to 38% (…) in forehead and chin area.“^[6]

Acetyl Hexapeptide-3 and Nociception

Acetyl Hexapeptide-3 has been examined in several in vitro models for its potential impact on various cellular and molecular mechanisms. This includes studying its potential on ion channels and inflammatory processes that are involved in the occurrence of nociceptive problems and hyperalgesia.

For example, studies have investigated the potential of the palmitoylated version of Acetyl Hexapeptide-3, called DD04107, for reducing nociceptive stimuli in models of chronic inflammatory and neuropathic hyperalgesia.^[7] More specifically, the research suggests that the palmitoylated version of Acetyl Hexapeptide-3 may inhibit the release of neuromodulators related to nociceptive signaling. It appears to do so by interfering with SNAP-25 and preventing these neuromodulators’ Ca(2+)-dependent exocytosis.As a result, the palmitoylated version of Acetyl Hexapeptide-3 may block the inflammatory recruitment of TRPV1 channels leading to its anti-hyperalgesia and anti-allodynic potential. 

TRPV1 channels are ion channels found predominantly on sensory nerve fibers, including those involved in pain perception. These channels appear to be activated by various stimuli, including heat, inflammatory mediators, and chemical irritants, and their activation is considered to lead to the generation and transmission of pain signals.

In studies using carrageenan-induced inflammation, which helps scientific models to mimic acute inflammatory pain, the palmitoylated version of Acetyl Hexapeptide-3 has been hypothesized to have anti-inflammatory activity by reducing paw volume (a measure of inflammation) and attenuating mechanical hypersensitivity.^[8]

Furthermore, the palmitoylated version of Acetyl Hexapeptide-3 has also been evaluated in models of chronic inflammatory pain, such as complete Freund’s adjuvant (CFA)-induced inflammation. In these models, the palmitoylated version of Acetyl Hexapeptide-3 appeared to mitigate thermal hyperalgesia and mechanical allodynia, indicating its potential for chronic inflammatory hyperalgesia.

The palmitoylated version of Acetyl Hexapeptide-3 has also been proposed to potentially reduce pain associated with peripheral neuropathy induced by various agents. 

Conclusion

Acetyl Hexapeptide-3, a synthetic peptide, may have promising potential in various scientific research areas. Its molecular mechanisms involve interacting with neurotransmitter release in neuromuscular synapses by acting as a competitive inhibitor of SNAP25, similar to bacterial toxins. This interference inhibits acetylcholine exocytosis, potentially preventing muscle cell contraction. Furthermore, Acetyl Hexapeptide-3 may impact collagen synthesis, leading to improvements in the topography of dermal structures and a potential reduction in scarring. Studies have also explored its role in nociception, indicating its potential to inhibit neuromodulators related to pain signaling and potentially improve chronic inflammatory and neuropathic hyperalgesia. 

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Grosicki, M., Latacz, G., Szopa, A., Cukier, A., & Kieć-Kononowicz, K. (2014). The study of cellular cytotoxicity of argireline – an anti-aging peptide. Acta biochimica Polonica, 61(1), 29–32.
2. Blanes-Mira, C., Clemente, J., Jodas, G., Gil, A., Fernández-Ballester, G., Ponsati, B., Gutierrez, L., Pérez-Payá, E., & Ferrer-Montiel, A. (2002). A synthetic hexapeptide (Argireline) with antiwrinkle activity. International journal of cosmetic science, 24(5), 303–310. https://doi.org/10.1046/j.1467-2494.2002.00153.x
3. Wang, Y., Wang, M., Xiao, X. S., Pan, P., Li, P., & Huo, J. (2013). The anti wrinkle efficacy of synthetic hexapeptide (Argireline) in Chinese Subjects. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology, Advance online publication. https://doi.org/10.3109/14764172.2012.759234
4. An, J. H., Lee, H. J., Yoon, M. S., & Kim, D. H. (2019). Anti-Wrinkle Efficacy of Cross-Linked Hyaluronic Acid-Based Microneedle Patch with Acetyl Hexapeptide-8 and Epidermal Growth Factor on Korean Skin. Annals of dermatology, 31(3), 263–271. https://doi.org/10.5021/ad.2019.31.3.263
5. Wang, Y., Wang, M., Xiao, X. S., Huo, J., & Zhang, W. D. (2013). The anti-wrinkle efficacy of Argireline. Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology, 15(4), 237–241. https://doi.org/10.3109/14764172.2013.769273
6. Palmieri, B., Noviello, A., Corazzari, V., Garelli, A., & Vadala, M. (2020). Skin scars and wrinkles temporary camouflage in dermatology and oncoesthetics: focus on acetyl hexapeptide-8. La Clinica terapeutica, 171(6), e539–e548. https://doi.org/10.7417/CT.2020.2270
7. Ponsati, B., Carreño, C., Curto-Reyes, V., Valenzuela, B., Duart, M. J., Van den Nest, W., Cauli, O., Beltran, B., Fernandez, J., Borsini, F., Caprioli, A., Di Serio, S., Veretchy, M., Baamonde, A., Menendez, L., Barros, F., de la Pena, P., Borges, R., Felipo, V., Planells-Cases, R., … Ferrer-Montiel, A. (2012). An inhibitor of neuronal exocytosis (DD04107) displays long-lasting in vivo activity against chronic inflammatory and neuropathic pain. The Journal of pharmacology and experimental therapeutics, 341(3), 634–645. https://doi.org/10.1124/jpet.111.190678
8. Butrón, D., Zamora-Carreras, H., Devesa, I., Treviño, M. A., Abian, O., Velázquez-Campoy, A., Bonache, M. Á., Lagartera, L., Martín-Martínez, M., González-Rodríguez, S., Baamonde, A., Fernández-Carvajal, A., Ferrer-Montiel, A., Jiménez, M. Á., & González-Muñiz, R. (2021). DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target. Bioorganic chemistry, 115, 105231. https://doi.org/10.1016/j.bioorg.2021.105231

Kisspeptin-10 peptide consists of 10 amino acids and has the sequence Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2. It shares the same C-terminal decapeptide sequence known as RFAmide (arginine-amidated phenylalanine) with the other processed kisspeptin sequences. Although Kisspeptin-10 has intrinsic bioactivity similar to the longer kisspeptin fragments, it is also been characterized by researchers to exhibit a shorter half-life and a more rapid onset of potential action.

Kisspeptin-10 Peptide and The Gonadotropic Axis

Kisspeptin-10 appears to potentially play a complex role in GnRH-producing hypothalamic cells. Researchers were investigating the potential impact of Kisspeptin-10 (KP-10) on gene expression in different types of hypothalamic cell lines.^[2] They suggested that in mHypoA-50 AVPV cells, Kisspeptin-10 may increase Kiss-1 mRNA and kisspeptin protein levels, possibly without affecting GnRH expression. In mHypoA-55 ARC cells, both kisspeptin genes and GnRH expression may be upregulated by Kisspeptin-10 peptide stimulation. Furthermore, Kisspeptin-10 appeared to elevate c-Fos protein levels, indicating potential neuronal activity in both cell lines. Similar apparent responses were observed in primary cultures of fetal rat neuronal cells.

Studies also suggest that Kisspeptin-10 may stimulate GnRH release in pre-pubescence and pubescence.^[3] Researchers have reported that there appeared to be a significant remodeling of the native kisspeptin and neurokinin B (NKB) signaling pathways when exposed to Kisspeptin-10. In fact, Kisspeptin-10 may interact with GnRH release via both NKB neurons and kisspeptin neurons. They also comment that there may be “a parallel increase in kisspeptin release and GnRH release during puberty.” Yet, the peptide did not appear to have any initiation potential regarding pubescence.

Researchers have also aimed to investigate the potential impact of Kisspeptin-10 on the production of progesterone (P4) in bovine granulosa cells (BGCs) and the role of microRNA 1246 (miR-1246) in this process.^[4] The scientists hypothesized that exposing BGCs to Kisspeptin-10 may increase the levels of P4, mRNA expression of the steroidogenesis-related gene StAR, and free cholesterol content. Simultaneously, it appeared to decrease the expression of miR-1246 in BGCs. Overexpressing miR-1246 may also inhibit P4 synthesis, StAR mRNA expression, and free cholesterol content in BGCs, while under-expressing miR-1246 may reverse this impact. Furthermore, overexpressing miR-1246 counteracted the enhancing potential of Kisspeptin-10 on P4 synthesis, StAR mRNA expression, and free cholesterol content in BGCs. Conversely, under-expressing miR-1246 appeared to amplify the enhancing potential of Kisspeptin-10. The study also indicated that miR-1246 targeted the 3’UTR of StAR in BGCs, suggesting that Kisspeptin-10 peptide promotes P4 synthesis in BGCs by facilitating the transport of free cholesterol through the regulation of miR-1246/StAR expression.

Kisspeptin-10 Peptide and Cholinergic Neurons

The accommodation of amyloid-β (Aβ) and α-synuclein (α-syn) in cholinergic neurons may potentially damage them. Yet, researchers suggest that Kisspeptin-10 may bind to Aβ extracellularly and thus potentially inhibit Aβ toxicity.^[5] The scientists comment that “The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists.” Based on similarities between α-syn’s non-amyloid-β component (NAC) and Aβ’s C-terminus, other researchers have also hypothesized that Kisspeptin-10 might also mitigate α-syn-induced toxicity in cholinergic neurons.^[6] They conducted experiments using cholinergic cells and commented that high concentrations of Kisspeptin-10 may increase toxicity, while low concentrations may potentially reduce both wild-type and E46K mutant α-syn-induced toxicity. The computational analysis supported these findings, indicating potentially favorable binding between Kisspeptin-10 and the C-terminal residues of α-syn. Molecular dynamics simulations also suggested the Kisspeptin-10-α-syn complexes had good stability. 

Scientists have continued to explore this topic, specifically whether GPR54 (the receptor for the kisspeptin gene) activation is necessary for the Kisspeptin-10 peptide binding potential to the C-terminal pockets of α-syn.^[7] To investigate this, ChAT-positive SH-SY5Y neurons were engineered to overexpress wild-type or E46K mutant α-syn, and the potential impact of Kisspeptin-10 on α-syn-induced neuronal death was evaluated using flow cytometry and immunocytochemistry. Kisspeptin-10 appeared to reduce apoptosis and mitochondrial damage caused by wild-type and E46K mutant α-syn in cholinergic neurons. Interestingly, the apparent neuroprotective potential of Kisspeptin-10 remained unaffected by combined presentation with a GPR54 antagonist, kisspeptin-234 (KP-234), indicating that GPR54 activation might not be essential for Kisspeptin-10’s action. Furthermore, the researchers commented that Kisspeptin-10 reduced α-syn and choline acetyltransferase (ChAT) immunoreactivity in neurons overexpressing wild-type and E46K mutant α-syn. 

Kisspeptin-10 Peptide and Orexigenic Stimuli

Scientists have aimed to explore the potential metabolic and orexigenic action of Kisspeptin-10peptide by examining its possible impact on gene expression of neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF), as well as the levels of dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxy indole acetic acid (5-HIIA) in hypothalamic cells (Hypo-E22).^[8] The results suggested that Hypo-E22 cells appear to tolerate Kisspeptin-10, and it may independently increase NPY gene expression, while BDNF expression appeared inhibited. Additionally, Kisspeptin-10 appeared to reduce 5-HT and DA levels, while NE levels reportedly remained unaffected. The apparent decrease in DA and 5-HT was consistent with increased ratios of DOPAC/DA and 5-HIIA/5-HT induced by the peptide. The apparent increase in NPY expression while reducing BDNF and 5-HT activity may support the orexigenic potential of  Kisspeptin-10.

Conclusion

In conclusion, Kisspeptin-10 peptide, derived from the cleavage of Kisspeptin-54, exhibits distinct characteristics compared to longer kisspeptin fragments. In vitro studies have shed light on its potential on the gonadotropic axis, cholinergic neurons, and orexigenic stimuli. Kisspeptin-10 appears to modulate gene expression and protein levels, potentially influencing neuronal activity and GnRH release. Moreover, it shows promise in mitigating the toxicity induced by amyloid-β and α-synuclein in cholinergic neurons. The peptide’s neuroprotective potential was observed independently of GPR54 activation, suggesting alternative mechanisms at play. Additionally, Kisspeptin-10 may impact gene expression and neurotransmitter levels related to its orexigenic potential.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Kotani, M., Detheux, M., Vandenbogaerde, A., Communi, D., Vanderwinden, J. M., Le Poul, E., Brézillon, S., Tyldesley, R., Suarez-Huerta, N., Vandeput, F., Blanpain, C., Schiffmann, S. N., Vassart, G., & Parmentier, M. (2001). The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. The Journal of biological chemistry, 276(37), 34631–34636. https://doi.org/10.1074/jbc.M104847200
2. Kanasaki, H., Tumurbaatar, T., Tumurgan, Z., Oride, A., Okada, H., & Kyo, S. (2021). Mutual Interactions Between GnRH and Kisspeptin in GnRH- and Kiss-1-Expressing Immortalized Hypothalamic Cell Models. Reproductive sciences (Thousand Oaks, Calif.), 28(12), 3380–3389. https://doi.org/10.1007/s43032-021-00695-z
3. Garcia, J. P., Keen, K. L., Seminara, S. B., & Terasawa, E. (2019). Role of Kisspeptin and NKB in Puberty in Nonhuman Primates: Sex Differences. Seminars in reproductive medicine, 37(2), 47–55. https://doi.org/10.1055/s-0039-3400253
4. Guo, L., Xu, H., Li, Y., Liu, H., Zhao, J., Lu, W., & Wang, J. (2022). Kisspeptin-10 Promotes Progesterone Synthesis in Bovine Ovarian Granulosa Cells via Downregulation of microRNA-1246. Genes, 13(2), 298. https://doi.org/10.3390/genes13020298
5. Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 2012 Sep 19;3(9):706-19. doi: 10.1021/cn300045d. Epub 2012 May 30. PMID: 23019497; PMCID: PMC3447396.
6. Simon, C., Soga, T., Ahemad, N., Bhuvanendran, S., & Parhar, I. (2022). Kisspeptin-10 Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro. International journal of molecular sciences, 23(9), 5193. https://doi.org/10.3390/ijms23095193
7. Simon, C., Soga, T., & Parhar, I. (2023). Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner. International journal of molecular sciences, 24(7), 6056. https://doi.org/10.3390/ijms24076056
8. Orlando, G., Leone, S., Ferrante, C., Chiavaroli, A., Mollica, A., Stefanucci, A., Macedonio, G., Dimmito, M. P., Leporini, L., Menghini, L., Brunetti, L., & Recinella, L. (2018). Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. Molecules (Basel, Switzerland), 23(12), 3071. https://doi.org/10.3390/molecules23123071

Like Semax, N-Acetyl Semax peptide has been studied for its neuroprotective and nootropic potential.^[2] It is hypothesized to increase levels of neurotrophic factors in the brain, such as Brain-Derived Neurotrophic Factor (BDNF). BDNF is considered important for neurons’ growth, survival, and maintenance. Upregulation of BDNF levels may have neuroprotective potential and act favorably on higher cerebral functions.

N-Acetyl Semax and BDNF

N-Acetyl Semax may have the ability to activate and elevate the levels of neurotrophic factors in the central nervous system, such as the Brain-Derived Neurotrophic Factor (BDNF). One clinical trial aimed to investigate the potential of the peptide on plasma BDNF levels, motor performance, and Barthel index score after ischemic nerve damage.^[3] According to the research, N-acetyl Semax presentation may increase BDNF plasma levels, accelerate the improvement and final outcome of Barthel score index speed functional recovery, and support motor performance. Moreover, the researchers reported that “There was a positive correlation between BDNF plasma levels and Barthel score, as well as a correlation between early rehabilitation and motor performance improvement.”

Another trial also suggests that N-Acetyl Semax may stimulate the synthesis of BDNF in astrocytes and potentially increase BDNF levels in the basal forebrain but not in the cerebellum.^[4] 

Apart from potentially increasing BDNF protein and mRNA levels in the central nervous system, some studies suggest that N-Acetyl Semax may also result in increased tyrosine phosphorylation levels of trkB.^[5] The researchers reported a “maximal 1.4-fold increase of BDNF protein levels accompanying with 1.6-fold increase of trkB tyrosine phosporylation levels, and a 3-fold and a 2-fold increase of exon III BDNF and trkB mRNA levels, respectively,” trkB (tropomyosin receptor kinase B) is a protein receptor found on the surface of certain neurons in the brain. It is the receptor for Brain-Derived Neurotrophic Factor (BDNF), which is considered by scientists to play an important role in neurons’ growth, survival, and maintenance. When BDNF binds to trkB, it appears to trigger a series of signaling events inside the neuron that may result in the strengthening of existing connections between neurons, the growth of new connections, and the survival of the neuron itself. The researchers suggest that this may potentially be accompanied by an increase in conditioned avoidance reactions, suggesting that N-Acetyl Semax may affect cognitive brain functions by modulating the BDNF/trkB system in the hippocampus.

In addition to BDNF, N-Acetyl Semax may potentially affect another neurotrophic factor called NGF – nerve growth factor. Researchers suggest that N-acetyl Semax may result in the activation of the expression of the NGF and BDNG genes in the hippocampus, frontal cortex, and retina, with multidirectional action.^[6] In particular, the expression of NGF and BDNF genes may first increase in the frontal cortex initially, while later, there may be an increase in the hippocampus and retina area.

N-Acetyl Semax and Cerebral Functioning

One study used resting-state fMRI to examine the potential of N-Acetyl Semax on the central nervous system’s default mode network (DMN).^[7] The use of fMRI (functional magnetic resonance imaging) is based on the registration of shifts in the blood oxygenation level-dependent parameters (BOLD signal) in nerve tissue. The study commented that soon after N-Acetyl Semax instillation, the volume of the DMN network’s frontal subcomponent appeared significantly increased. The study also suggested the potential topographic locus of the actions of N-Acetyl Semax in the frontal compartments. The researchers noted that “The increase in the DMN frontal subcomponent in the main group was presented by a large cluster including the paracingular gyrus, frontal cingular cortex, and frontal pole.” This increase in spatial volumes of DMN subcomponents under the influence of N-Acetyl Semax may be due to the involvement of a greater number of neuronal populations in the network due to the synchronization of activity.

Another trial investigated the potential of N-Acetyl Semax on higher cerebral function and electroencephalography (EEG) patterns during cognitive activity.^[8] The study commented that Semax had a favorable impact on attention and short-term memory performance. EEG analysis suggested that Semax decreased delta rhythm and increased alpha and beta rhythms, indicating its anti-amnesic and nootropic potential.

N-Acetyl Semax and Gastric Mucosa

Some experiments suggest that N-acetyl Semax may also exert actions outside nervous tissues. Some studies suggest that the peptide may accelerate the clarification of ulcers from necrotic tissues and activate the process of cicatrization and epithelization.^[9] Other experiments suggest that this protective potential may be due to N-Acetyl Semax preventing the action of negative factors that would otherwise disrupt and reduce the normal blood flow to the gastric mucosa and result in ulcerogenesis.^[10]

Conclusion

In conclusion, N-Acetyl Semax is a synthetic peptide based on the structure of the naturally occurring ACTH and is additionally acetylated to increase its stability possibly. 

The peptide may potentially increase levels of neurotrophic factors in the brain, such as BDNF and NGF, which are considered important for the growth, survival, and maintenance of neurons. Upregulation of BDNF levels may have neuroprotective potential and act favorably on higher cerebral functions. 

Furthermore, N-Acetyl Semax potentially exerts actions outside nervous tissues, such as accelerating the clarification of ulcers from necrotic tissues and activating the cicatrization and epithelization in gastric mucosa.

However, further studies are needed to confirm these potential actions of N-Acetyl Semax.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Magrì, A., Tabbì, G., Giuffrida, A., Pappalardo, G., Satriano, C., Naletova, I., Nicoletti, V. G., & Attanasio, F. (2016). Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. Journal of inorganic biochemistry, 164, 59–69. https://doi.org/10.1016/j.jinorgbio.2016.08.013
2. Kurysheva, N. I., Shpak, A. A., Ioĭleva, E. E., Galanter, L. I., Nagornova, N. D., Shubina, N. I.u, & Shlyshalova, N. N. (2001). “Semaks” v lechenii glaukomatoznoĭ opticheskoĭ neĭropatii u bol’nykh s normalizovannym oftal’motonusom [Semax in the treatment of glaucomatous optic neuropathy in patients with normalized ophthalmic tone]. Vestnik oftalmologii, 117(4), 5–8.
3. Gusev, E. I., Martynov, M. Y., Kostenko, E. V., Petrova, L. V., & Bobyreva, S. N. (2018). Éffektivnost’ semaksa pri lechenii bol’nykh na raznykh stadiiakh ishemicheskogo insul’ta [The efficacy of semax in the tretament of patients at different stages of ischemic stroke]. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova, 118(3. Vyp. 2), 61–68. https://doi.org/10.17116/jnevro20181183261-68
4. Dolotov, O. V., Karpenko, E. A., Seredenina, T. S., Inozemtseva, L. S., Levitskaya, N. G., Zolotarev, Y. A., Kamensky, A. A., Grivennikov, I. A., Engele, J., & Myasoedov, N. F. (2006). Semax, an analogue of adrenocorticotropin (4-10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal forebrain. Journal of neurochemistry, 97 Suppl 1, 82–86. https://doi.org/10.1111/j.1471-4159.2006.03658.x
5. 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
6. Shadrina, M., Kolomin, T., Agapova, T., Agniullin, Y., Shram, S., Slominsky, P., Lymborska, S., & Myasoedov, N. (2010). Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action. Journal of molecular neuroscience : MN, 41(1), 30–35. https://doi.org/10.1007/s12031-009-9270-z
7. Lebedeva, I. S., Panikratova, Y. R., Sokolov, O. Y., Kupriyanov, D. A., Rumshiskaya, A. D., Kost, N. V., & Myasoedov, N. F. (2018). Effects of Semax on the Default Mode Network of the Brain. Bulletin of experimental biology and medicine, 165(5), 653–656. https://doi.org/10.1007/s10517-018-4234-3
8. Kaplan, A. Y. A., Kochetova, A. G., Nezavibathko, V. N., Rjasina, T. V., & Ashmarin, I. P. (1996). Synthetic acth analogue semax displays nootropic‐like activity in humans. Neuroscience Research Communications, 19(2), 115-123.
9. Zhuĭkova, S. E., Badmaeva, K. E., Samonina, G. E., & Plesskaia, L. G. (2003). Semaks i nekotorye gliprolinovye peptidy uskoriaiut zazhivlenie atsetatnykh iazv u krys [Semax and some glyproline peptides accelerate the healing of acetic ulcers in rats]. Eksperimental’naia i klinicheskaia gastroenterologiia = Experimental & clinical gastroenterology, (4), 88–117.
10. Zhuikova, S. E., Sergeev, V. I., Samonina, G. E., & Myasoedov, N. F. (2002). Possible mechanism underlying the effect of Semax on the formation of indomethacin-induced ulcers in rats. Bulletin of experimental biology and medicine, 133(6), 577–579. https://doi.org/10.1023/a:1020285909696

This peptide appears to be naturally produced in the hypothalamus, where it is also known as gonadotropin-releasing hormone (GnRG), and may be rapidly degraded by enzymes called proteases. Gonadorelin appears to be a ligand for the receptors called gonadotropin-releasing hormone receptors (GnRH receptors), located on the surface of cells in the anterior pituitary gland.^[1] These receptors are members of the G protein-coupled receptor (GPCR) family, which scientists characterize by their seven-transmembrane domain structure. 

Activation of GnRH receptors appears to trigger intracellular signaling pathways, including the cyclic adenosine monophosphate (cAMP) pathway and the phospholipase C (PLC) pathway. These signaling pathways appear to be major regulators of the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. Research indicates that these hormones may be pivotally involved in the maturation and release of eggs in the ovaries and testosterone production. 

Gonadorelin (GnRH) and Gonadotropins

Gonadorelin exhibits apparent potential to bind to GnRH receptors located on pituitary cells, which may trigger a signaling cascade resulting in the transcription modulation of genes within the target cell. GnRH receptors are Gq-protein coupled, and their activation may induce the formation of receptor clusters that become internalized into the cell. Researchers should note that the GnRH receptors’ relatively short intracellular carboxy-terminal tail may prevent rapid desensitization.^[2]

According to research, two potential modes of Gonadorelin action on gonadotropins are pulsatile and surge modes.^[3] Pulsatile mode refers to periodic action, with clear pulses of gonadorelin into the portal circulation, while it remains undetectable between pulses. In female species, the surge mode of gonadorelin appears to occur during the preovulatory phase, where it may continuously present in the portal circulation.

Furthermore, researchers suggest that Gonadorelin may have different stimulatory actions on LH and FSH secretion, with FSH secretion being more irregular due to differences in storage, response times, and other factors. Pulsatile secretion of LH appears to be more strongly associated with Gonadorelin, while FSH has a constitutive secretion. The frequency of Gonadorelin pulses may selectively regulate gene transcription, with rapid pulses promoting LH formation and slow pulses promoting FSH formation.^[4]

Moreover, scientists hypothesize that after apparent initial stimulation of FSH and LH, continuous exposure to Gonadorelin either downregulates its receptors or its signaling pathway in pituitary cells.^[5] This hypothesis is based on observations that when the receptors appear to be exposed to a continuous action by gonadorelin, the “GnRH agonist (…) can actually act as an inhibitory agonist, thus reducing gonadotropin secretion.”

Gonadorelin (GnRH) and The Estrous Cycle

Scientists suggest two potential models of Gonadorelin’s action on the estrous cycle: the deterministic and permissive models. The deterministic model suggests that increasing Gonadorelin secretion may induce ovulation. In contrast, the permissive model suggests that the preovulatory LH surge may result from increased pituitary sensitivity to Gonadorelin without necessarily an increase in gonadorelin secretion. Studies in rodents, rabbits, and sheep support the deterministic model, while studies in primates suggest the permissive model may be correct.^[6]

Regardless, research experiments across various animal models point to Gonadorelin’s likely role in the estrous cycle. One animal study aimed to evaluate its potential to induce ovulation in female cats.^[7] The study divided 27 female cats into a Gonadorelin group and a placebo group that received saline solution. Results suggested that 84% of the female cats which received Gonadorelin had ovulated, while only 37% of the placebo group had ovulated. 

One trial also aimed to assess the action of Gonadorelin on premature ovarian failure (POF) compared to a placebo for four weeks. The scientists posited that apparently, 20% of the agonist group ovulated, compared to none in the placebo group.^[8] They also commented that “Follicular growth was seen in five [..] of the agonist group and in four [..] of the placebo group.” Premature ovarian failure is a condition in which the ovaries stop functioning too early. This may result in infertility, amenorrhea, dyspareunia, hyperhidrosis, etc. The cause of premature ovarian failure is not always known, but genetic factors, autoimmune disorders, and certain infections may induce it. 

Gonadorelin (GnRH) and The Nervous System

Research indicates that Gonadorelin and GnRH receptors are present in different brain areas and may induce various actions. Studies hypothesize that Gonadorelin may increase the expression of cytoskeletal proteins and promote neuronal outgrowth in the cerebral cortex since GnRH receptors appear abundant amongst the neurons in these areas of the brain.^[9]

Gonadorelin may also alter neural circuitry underlying visual working memory, but the mechanism of action is unclear. In the cerebellum, Gonadorelin and GnRH receptors have been reportedly detected in Purkinje cells and are suggested to potentially affect both glutamate and GABA content. In turn, this suggests a potential role in regulating their interactions. 

Finally, high densities of GnRH receptors have been detected in the CA1-CA3 regions of the hippocampus, and activation of these receptors has been proposed to affect sexual behavior regulation in mammals, as well as an increase in intrinsic neuronal excitability and synaptic transmission.

Conclusion

Gonadorelin is a decapeptide that may play a role in the hypothalamic-pituitary-gonadal axis. Its potential to bind to gonadotropin-releasing hormone receptors may trigger intracellular signaling pathways that regulate the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. 

Gonadorelin also appears to play an essential role in the estrous cycle and especially its ovulatory phase, which may be potentially due to a peak in its levels or a peak in a change in the sensitivity of the gonadotropin-releasing hormone receptors. Moreover, the presence of Gonadorelin and GnRH receptors in various brain regions suggests that it may have neuromodulatory action beyond its well-known role in gonadotropin release and the estrous cycle.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Perrett, R. M., & McArdle, C. A. (2013). Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network. Frontiers in endocrinology, 4, 180. https://doi.org/10.3389/fendo.2013.00180
2. Casteel CO, Singh G. Physiology, Gonadotropin-Releasing Hormone. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558992/
3. Maeda, K., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H., & Okamura, H. (2010). Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain research, 1364, 103–115. https://doi.org/10.1016/j.brainres.2010.10.026
4. Marques P, Skorupskaite K, Rozario KS, et al. Physiology of GnRH and Gonadotropin Secretion. [Updated 2022 Jan 5]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279070/
5. Jones, R. E., & Lopez, K. H. (2013). Human reproductive biology. Academic Press.
6. Karsch, F. J., Bowen, J. M., Caraty, A., Evans, N. P., & Moenter, S. M. (1997). Gonadotropin-releasing hormone requirements for ovulation. Biology of reproduction, 56(2), 303–309. https://doi.org/10.1095/biolreprod56.2.303
7. Ferré-Dolcet, L., Frumento, P., Abramo, F., & Romagnoli, S. (2021). Disappearance of signs of heat and induction of ovulation in oestrous queens with gonadorelin: a clinical study. Journal of feline medicine and surgery, 23(4), 344–350. https://doi.org/10.1177/1098612X20951284
8. van Kasteren, Y. M., Hoek, A., & Schoemaker, J. (1995). Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation. Fertility and sterility, 64(2), 273–278. https://doi.org/10.1016/s0015-0282(16)57722-x
9. Martínez-Moreno, C. G., Calderón-Vallejo, D., Harvey, S., Arámburo, C., & Quintanar, J. L. (2018). Growth Hormone (GH) and Gonadotropin-Releasing Hormone (GnRH) in the Central Nervous System: A Potential Neurological Combinatory Therapy?. International journal of molecular sciences, 19(2), 375. https://doi.org/10.3390/ijms19020375

Scientists consider TREK-1 to be widely expressed in the central nervous system,  playing a possible role in pain perception, mood regulation, and neuroprotection. PE-22-28 has exhibited potential binding activity to the extracellular domain of TREK-1, thereby inhibiting the channel’s activity. Further research is needed to fully understand the mechanisms of action and potential research applications of PE-22-28 peptide. PE 22–28 has also been used as the core peptide to design other analogs with different N- and C-terminal end modifications. 

PE-22-28 Peptide and TREK-1 Inhibition

The primary potential  mechanism of action of PE-22–28 peptide is considered by researchers to be exerted via blocking the TREK-1 channels in the central nervous system. According to Djillani et al., PE-22–28 is “the shortest, most efficient sequence capable of blocking the TREK-1 channel with higher potency” than spadin.^[2] TREK-1 is generally the most studied background two-pore domain potassium channel. Its main role is considered to be controling cell excitability and maintaining the membrane potential below the threshold of depolarization.^[3] TREK-1 may also be multi-regulated by a variety of physical and chemical stimuli. TREK-1 has also been reported in the heart and several other organs, but inhibition of these channels has unknown impact.^[4]

By blocking TREK-1, murine studies suggest that PE-22–28 may significantly decrease immobility time in the forced swim test (FST) compared to control mice that received saline.^[1] The FST is a common test used to measure depressive behavior in rodents, where the mice are placed in a water tank, and their mobility is monitored. In addition, the study also evaluated the potential of PE-22–28 on the learned helplessness test (LHT), another test with similar indications as FST. The LHT measures the time it takes for mice to escape from an aversive stimulus. The study commented that the sub-chronic presentation of PE-22–28 appears to significantly reduce the escape latencies in the LHT.

Furthermore, the trial evaluated the potential of PE-22-28 on a mice model of long-term corticosterone presentation.^[1] Corticosterone is a hormone that is involved in the body’s response to stress, and chronic exposure to high levels of corticosterone has been associated with depressive behavior in rodents. The results of this study suggested that PE-22–28 peptide may result in decreasing immobility time in the FST. It may also reduce the latency to eat in the novelty-suppressed feeding (NSF) test, which measures an animal’s willingness to eat in a stressful environment.

PE-22-28 Peptide and Serotonin Transmission

Researchers posit that PE-22–28 may inhibit TREK-1, possibly leading to the excitation of the dorsal raphé nucleus and the firing of serotonin transmission.^[5] The researchers suggest that “if a viral vector that leads to the secretion of PE 22-28 is [presented to] the dorsal raphé nucleus, the peptide will block the channel and thereby activate the serotonergic neurons, resulting in the facilitation of serotonergic transmission, as SSRIs do.”

Studies suggest that PE-22–28 peptide may act as a blocker of the TREK-1 channel, similar to spadin, and Maati et al. investigated these actions in relation to the connectivity between the medial prefrontal cortex (mPFC) and dorsal raphé serotonergic neurons.^[6] The study commented that spadin might increase the firing rate of serotonin neurons and that the action of spadin and 5-HT4 agonists appeared additive and independent of each other. However, adding a mGluR2/3 antagonist reportedly blocked the action of spadin, suggesting that spadin likely depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors. Therefore, the researchers further suggested that PE-22-28 may also interact with the mGluR2/3 receptors, similar to spadin, to fire up the serotonin neurons. 

The mGluR2/3 is a metabotropic glutamate receptor found in the central nervous system. They are G protein-coupled receptors that are considered to be activated by the neurotransmitter glutamate. There are two subtypes of mGluR2/3 receptors: mGluR2 and mGluR3, and they are both involved in regulating neurotransmitter release.^[7] Activation of mGluR2/3 receptors appears to inhibit the release of glutamate and other neurotransmitters, such as GABA and dopamine. This mechanism may help to regulate synaptic transmission and maintain the balance of excitatory and inhibitory neurotransmission in the brain. The study also suggested that the combination of 5-HT activators should be cautiously approached.^[6]

PE-22-28 Peptide and Neuroplasticity

One in vitro trial suggested that inhibiting TREK-1 may increase neuronal membrane potential and activate both MAPK and PI3K signaling pathways in a time- and concentration-dependent manner.^[8] The latter pathway has been linked to the supposed protective action of spadin against apoptosis. Inhibiting TREK-1 also appeared to enhance mRNA expression and protein levels of two markers of synaptogenesis, PSD-95, and synapsin. Inhibiting TREK-1 may increase the proportion of mature spines in cortical neurons, suggesting increased neuroplasticity. Inhibiting TREK-1 appeared in other experimental models to increase mRNA expression and protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, suggesting a neuroplasticity potential.^[8]

In one murine model, PE-22-28 was presented for 4 days, and on the 5th day, the brains of the rats were analyzed.^[1] The results suggested that PE-22-28 significantly increased the number of bromodeoxyuridine (BrdU) positive cells in the hippocampus compared with saline mice, suggesting that PE-22-28 may induce hippocampal neurogenesis similar to spadin. BrdU is a thymidine analog that incorporates the DNA of dividing cells during the S-phase of the cell cycle.

Conclusion

PE-22-28 is a synthetic peptide analogous to spadin, a protein naturally produced in the central nervous system and considered by researchers to possibly inhibit the action of TREK-1. As a result, the peptide appears to upregulate serotonin production, possibly improving neuroplasticity and reducing depressive behavior in animal models. Nevertheless, more research is needed to evaluate its potential actions.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Djillani, A., Pietri, M., Moreno, S., Heurteaux, C., Mazella, J., & Borsotto, M. (2017). Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Frontiers in pharmacology, 8, 643. https://doi.org/10.3389/fphar.2017.00643
2. Djillani, A., Pietri, M., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacology & therapeutics, 194, 185–198. https://doi.org/10.1016/j.pharmthera.2018.10.003
3. Djillani, A., Mazella, J., Heurteaux, C., & Borsotto, M. (2019). Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Frontiers in pharmacology, 10, 379. https://doi.org/10.3389/fphar.2019.00379
4. Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, Lazdunski M. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 1996 Dec 16;15(24):6854-62. PMID: 9003761; PMCID: PMC452511.
5. Okada, M., & Ortiz, E. (2022). Viral vector-mediated expressions of venom peptides as novel gene therapy for anxiety and depression. Medical Hypotheses, 166, 110910.
6. Moha ou Maati, H., Bourcier-Lucas, C., Veyssiere, J., Kanzari, A., Heurteaux, C., Borsotto, M., Haddjeri, N., & Lucas, G. (2016). The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function. Brain structure & function, 221(1), 21–37. https://doi.org/10.1007/s00429-014-0890-x
7. Jin LE, Wang M, Galvin VC, Lightbourne TC, Conn PJ, Arnsten AFT, Paspalas CD. mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks. Cereb Cortex. 2018 Mar 1;28(3):974-987. doi: 10.1093/cercor/bhx005. PMID: 28108498; PMCID: PMC5974790.
8. Devader, C., Khayachi, A., Veyssière, J., Moha Ou Maati, H., Roulot, M., Moreno, S., Borsotto, M., Martin, S., Heurteaux, C., & Mazella, J. (2015). In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin. British journal of pharmacology, 172(10), 2604–2617. https://doi.org/10.1111/bph.13083