PE-22-28
Cognitive & NootropicResearch Use OnlyLast reviewed: September 28, 2026
Quick Facts
- What it is
- A synthetic seven-amino-acid shortened analog of spadin (PE 12-28), a sortilin-derived natural peptide that blocks the TREK-1 potassium channel — an original target in depression research.
- How it's taken
- Not established in humans — the published route is intraperitoneal injection in mice
- Half-life
- Not characterized — the published figure is a DURATION OF ACTION in mice, about 23 hours against spadin's 7, which is not a half-life
- Typical research dose
- No human dose exists — published regimens are mouse protocols at microgram-per-kilogram scale
- Research status
- Preclinical only. No approval anywhere, no human study located, and zero registered trials for it or for spadin.
On this page
Where to source PE-22-28
PE-22-28 has no approved use anywhere and is sold by specialty research peptide vendors as material for laboratory use only. Prof. Peptide's price data currently tracks one vendor for this compound. A Certificate of Analysis is the only identity and purity check available to a buyer.
What is PE-22-28?
PE-22-28 is a synthetic seven-amino-acid peptide, and it exists because of a specific problem. Spadin — a 17-amino-acid natural peptide derived from sortilin/NTSR3, written PE 12-28 — blocks the TREK-1 potassium channel, an unusual and original target in depression research, and it works fast: within about four days, against the three to four weeks a classical antidepressant such as fluoxetine needs. Its weakness was that its activity disappeared in vivo beyond about seven hours. PE 22-28 was built from a study of what spadin actually degrades into in blood, to keep the activity and lose the fragility.
This compound is preclinical only. Mice and cells, and nothing else, since 2017. No human trial, no observational study, no case report, and no registered study on ClinicalTrials.gov for PE-22-28 or for spadin. The mechanism work is genuinely good and the target is interesting; neither of those things is human evidence, and this page does not treat them as such. New to peptide research? Start with the basics
Reported in the cited studies: TREK-1 block at an IC50 of 0.12 nM on hTREK-1/HEK cells, against 40–60 nM for spadin [1]; reduced immobility in the mouse forced swimming test and reduced latency to eat in the novelty suppressed feeding test after four days of sub-chronic treatment [1]; neurogenesis after four days and raised PSD-95 expression in mouse cortical neurons [1]; and a duration of action reaching about 23 hours against spadin's 7 [1].
The library's other Cognitive & Nootropic entries include Semax, Selank and Adamax.
How does PE-22-28 work?
This is one of the better-specified mechanisms among research peptides, and it is worth separating the mechanistic claim, which is well supported, from the therapeutic claim, which is untested in people.
- The TREK-1 target [3][4]. TREK-1 is a two-pore potassium channel, and blocking it is an original approach to depression — distinct from the monoamine mechanisms classical antidepressants work through. Spadin, a 17-amino-acid peptide derived from sortilin/NTSR3, was described as a natural TREK-1 blocker with antidepressant properties.
- The stability problem [2][3]. Spadin's activity did not persist: in vivo it disappeared beyond about seven hours. That single limitation drove the whole analog programme — cyclisation, shortening, and retro-inverso rebuilds, the last of which was reported to increase antidepressant effects in its own right (Veyssiere et al. 2015).
- PE 22-28, designed from spadin's own degradation [1]. Rather than guessing, the authors studied what spadin broke down into in blood and built a seven-amino-acid peptide from that. In patch-clamp work on hTREK-1/HEK cells it blocked TREK-1 with an IC50 of 0.12 nM against spadin's 40–60 nM, and its action lasted up to about 23 hours (Djillani et al. 2017).
- Downstream effects reported in mice [1]. Four days of treatment induced neurogenesis, and in mouse cortical neurons PE 22-28 and its derivatives raised PSD-95 expression, a marker of synaptogenesis.
What is PE-22-28 researched for, and what is missing?
The research is coherent, recent enough, and comes from a laboratory with a long programme behind it. It is also entirely preclinical, and the gap between where it stops and where a reader might assume it reaches is the most important thing on this page.
- Antidepressant-like activity in mice [1]. Reduced immobility in the forced swimming test, and reduced latency to eat in the novelty suppressed feeding test after four days of sub-chronic treatment (Djillani et al. 2017). These are rodent screening assays, not clinical outcomes.
- Potency at the target [1]. IC50 0.12 nM on hTREK-1/HEK cells, several hundredfold better than spadin in the same assay.
- Speed, as a class property [3]. The review reports spadin acting within four days against the three to four weeks fluoxetine requires — the property that makes this target interesting in the first place.
- Stroke and post-stroke depression, with a naming caveat [5]. A 2019 mouse stroke study reports protection from dopaminergic degeneration and post-stroke depression using "mini-spadin"; the indexed abstract does not name it PE 22-28, so it is reported here as adjacent work rather than as this compound's result.
- No human data at all. No trial, no observational study, no case report. ClinicalTrials.gov returns zero registered studies for PE-22-28 or spadin; the same query returns 788 for semaglutide, so the probe works. One term, "PE 22-28" with a space, returns 27 records — inspected and found to be unrelated studies matched on loose tokens, not trials of this compound.
How is PE-22-28 dosed, and what is known about safety?
No human dose exists, and the safety information is reported here in the same section rather than separately, because both answers come from the same small body of mouse work and neither can be read as a human finding.
The published regimens are mouse protocols: four-day sub-chronic treatment in the behavioural and neurogenesis experiments [1], and, in the adjacent stroke work, intraperitoneal doses of 0.03 µg/kg as a single low dose and 3 µg/kg once daily [5]. Microgram-per-kilogram figures in a mouse do not convert to a human schedule, so Prof. Peptide publishes no dose, frequency or route. On safety the position is simple and should not be softened: there is no human safety data for PE-22-28 — no adverse-event record in people, no interaction data, no pharmacokinetics, no long-term follow-up. The 2017 paper reports tolerability only in the narrow sense that its mouse experiments ran to completion. One property is worth naming precisely rather than reassuringly: the analog programme's stated purpose was to make the peptide last LONGER in the body, and PE 22-28's action duration reached about 23 hours against spadin's 7. Longer action is the design goal and also the direction in which an unwanted effect would persist. Research vendors sell PE-22-28 as lyophilised material labelled for laboratory use only; a Certificate of Analysis is the only identity and purity check available to a buyer.
What are the limitations of PE-22-28 research?
It is preclinical only. Mice and cells, and nothing else, since the compound was described in 2017. There is no registered clinical trial for it or for its parent spadin.
The efficacy evidence rests on rodent behavioural screening assays. The forced swimming test and the novelty suppressed feeding test are the standard first filters in antidepressant research, and their usefulness is in ruling compounds out rather than in predicting that one will work in a person. Depression research in particular has a long record of compounds that cleared these tests and then failed.
Almost all of the work comes from one laboratory group in France — the group that described spadin in the first place. That is normal for an early-stage target and it is not a criticism of the science; it does mean the findings have not been independently reproduced elsewhere.
PE-22-28 is not approved by the FDA, the EMA or any comparable regulator, for any indication. It is research-use-only material. Other compounds in this part of the library include Semax and Selank.
PE-22-28 FAQ
What is PE-22-28?
PE-22-28 is a synthetic seven-amino-acid peptide — a shortened analog of spadin, a 17-amino-acid natural peptide derived from sortilin/NTSR3 that blocks the TREK-1 potassium channel. Spadin itself is written PE 12-28; PE 22-28 is the fragment its designers built after studying spadin's own blood degradation products, looking for something that survived longer in the body.
Has PE-22-28 been tested in humans?
No. Prof. Peptide located no human study of PE-22-28 of any design — no trial, no observational report, no case series. The published work is mouse behavioural experiments, mouse cortical neuron cultures and patch-clamp electrophysiology on a human TREK-1 cell line. A ClinicalTrials.gov search returns zero registered studies for PE-22-28 or for spadin, against 788 for semaglutide on the same query, so the zero is a finding rather than a broken search.
What did the 2017 study actually find?
Patch-clamp work on hTREK-1/HEK cells reported PE 22-28 blocking TREK-1 with an IC50 of 0.12 nM, against 40–60 nM for spadin itself — several hundred times more potent in that assay. In mice, it reduced immobility time in the forced swimming test, and after four days of sub-chronic treatment reduced the latency to eat in the novelty suppressed feeding test. Four days of treatment induced neurogenesis, and in mouse cortical neurons the peptide raised PSD-95 expression, a synaptogenesis marker. Its duration of action ran to about 23 hours against roughly 7 for spadin.
Is PE-22-28 an antidepressant?
It has antidepressant-like activity in rodent behavioural models, which is not the same claim. The forced swimming test and novelty suppressed feeding test are screening assays: they detect a signal that many compounds produce, including some that later fail in people. TREK-1 is a genuinely original target in depression, and the mechanism work behind it is solid. Whether any of that translates to a human effect is untested.
Is there a standard PE-22-28 dose?
No. There is no approved or validated dose, because no human study has been published to establish one. The published regimens are mouse protocols given intraperitoneally at microgram-per-kilogram scale in specific experiments, and they do not convert to a human schedule by arithmetic.
References
- Djillani A, Pietri M, Moreno S, et al. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity. Front Pharmacol. 2017;8:643. doi:10.3389/fphar.2017.00643. PMID 28955242. https://pubmed.ncbi.nlm.nih.gov/28955242/
- Veyssiere J, Moha Ou Maati H, Mazella J, et al. Retroinverso analogs of spadin display increased antidepressant effects. Psychopharmacology (Berl). 2015;232(3):561-574. doi:10.1007/s00213-014-3683-2. PMID 25080852. https://pubmed.ncbi.nlm.nih.gov/25080852/
- Djillani A, Pietri M, Mazella J, et al. Fighting against depression with TREK-1 blockers: past and future. A focus on spadin. Pharmacol Ther. 2019;194:185-198. doi:10.1016/j.pharmthera.2018.10.003. PMID 30291907. https://pubmed.ncbi.nlm.nih.gov/30291907/
- Mazella J, Borsotto M, Heurteaux C. The involvement of sortilin/NTSR3 in depression as the progenitor of spadin and its role in the membrane expression of TREK-1. Front Pharmacol. 2018;9:1541. doi:10.3389/fphar.2018.01541. PMID 30670975. https://pubmed.ncbi.nlm.nih.gov/30670975/
- Pietri M, Djillani A, Mazella J, et al. First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. Neuropharmacology. 2019;158:107715. doi:10.1016/j.neuropharm.2019.107715. PMID 31325429. Tests “mini-spadin”; the indexed abstract does not name it PE 22-28. https://pubmed.ncbi.nlm.nih.gov/31325429/
Published Studies
Plain-English summaries of the peer-reviewed studies behind the statements above. Click any title to read the source paper. Every one is a cell-culture or mouse study; none involves human subjects.
Djillani A, Pietri M, Moreno S, et al.
The paper that designed PE 22-28, and the only PubMed record that names it. Starting from spadin's blood degradation products, the authors built a seven-amino-acid peptide and tested it by patch clamp on hTREK-1/HEK cells: IC50 0.12 nM, against 40–60 nM for spadin. In mice, PE 22-28 and its derivatives reduced immobility in the forced swimming test; after four days of sub-chronic treatment it significantly reduced latency to eat in the novelty suppressed feeding test; four days of treatment induced neurogenesis, with the G/A-PE 22-28 derivative most prominent; and in mouse cortical neurons the peptides raised PSD-95 expression. Duration of action reached about 23 hours against roughly 7 for spadin. All in vitro and mouse work.
Veyssiere J, Moha Ou Maati H, Mazella J, et al.
The earlier arm of the same optimisation effort: instead of shortening spadin, this work rebuilt it in a retro-inverso configuration — D-amino acids in reversed order — to resist degradation, and reported increased antidepressant effects. It is included because it shows the design problem PE 22-28 was solving. Spadin worked and did not last; several strategies were tried against that one limitation.
Djillani A, Pietri M, Mazella J, et al.
A review from the originating group, and the clearest statement of the case for this target. Spadin is a 17-amino-acid peptide blocking TREK-1, an original target in depression; it acts within four days against the three to four weeks a classical antidepressant such as fluoxetine requires, and its effects are associated with increased neurogenesis and synaptogenesis. Its weakness is in vivo stability of under seven hours, and the review surveys the retro-inverso, cyclisation and shortening strategies developed against that — the family PE 22-28 belongs to.
Mazella J, Borsotto M, Heurteaux C.
Background on where spadin comes from: sortilin/NTSR3, and its role in the membrane expression of the TREK-1 channel. Useful for understanding why a peptide derived from a receptor's propeptide would block a potassium channel at all, which is otherwise an odd-looking mechanism.
Pietri M, Djillani A, Mazella J, et al.
Listed with a caveat attached. This mouse stroke study tests "mini-spadin" — the same group's shortened spadin analog — at 0.03 µg/kg intraperitoneally and at 3 µg/kg once daily, reporting prevention of body-weight loss and of delayed dopaminergic degeneration in the substantia nigra, improved motor and cognitive deficits after ischemia, and prevention of post-stroke depression. The indexed abstract does not state that mini-spadin is PE 22-28, so Prof. Peptide reports this as adjacent work on the same group's shortened analog rather than as a PE-22-28 result.
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