PE-22-28

Origin and structure

PE-22-28 is derived from sortilin, a receptor protein also known as neurotensin receptor 3. As sortilin matures inside the cell, the enzyme furin cuts a 44-amino-acid piece off its front end. That piece is the propeptide, abbreviated PE, and it is released into the blood. In 2010 French researchers led by Jean Mazella, Marc Borsotto and Catherine Heurteaux described spadin: a 17-amino-acid section of the propeptide (positions 12 to 28) that blocks the TREK-1 potassium channel and behaved as a fast-acting antidepressant in mice.

Spadin's effect in mice was gone within about seven hours of an injection, so in 2017 the group, based at the CNRS Institut de Pharmacologie Moléculaire et Cellulaire in Valbonne near Nice, looked for a shorter version that would last longer. Starting from the fragments that spadin breaks down into in mouse serum, they tested ever shorter pieces and found that its last seven amino acids, positions 22 to 28 of the propeptide, were the shortest stretch that still blocked TREK-1 well. That heptapeptide, Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR), is PE 22-28; the group's later papers call it mini-spadin. The name simply means propeptide, residues 22 to 28.

As a free peptide PE 22-28 has the formula C35H55N11O9 and a molar mass of 773.9 g/mol (PubChem CID 165437303, CAS 1801959-12-5). In the same 2017 paper the researchers made 16 variants by modifying its ends or swapping amino acids, and kept two of them for further tests: G/A-PE 22-28, in which the first glycine is replaced by alanine (AVSWGLR), and a biotin-tagged version of that.

How it is thought to work

TREK-1 is a two-pore-domain potassium channel found in many tissues, including the brain. When it is open, potassium leaks out of the cell, which stabilises the membrane potential and keeps a neuron less excitable. Mice in which the TREK-1 gene was switched off behaved in depression tests as if they were on an antidepressant, with stronger serotonin signalling and more new neurons in the hippocampus, which made TREK-1 blockers candidate antidepressants. Fluoxetine also blocks TREK-1, but only at micromolar concentrations.

In recordings on human TREK-1 expressed in cultured HEK cells, PE 22-28 at 100 nM reduced the channel's current by about 55%. Its IC50, the concentration that halves the current, was about 0.1 nM (the paper gives 0.10 nM in some places and 0.12 nM in others), against about 40 nM for spadin. At 100 nM it had no effect on four related potassium channels (TREK-2, TRAAK, TRESK and TASK-1), and at 10 µM neither PE 22-28 nor its two variants blocked hERG, the heart channel linked to dangerous drug-induced rhythm disturbances. Like spadin, PE 22-28 blocked TREK-1 much better once the channel had been opened by arachidonic acid, a fatty acid that activates it.

An independent laboratory at the University of Portsmouth found that spadin is not a simple pore blocker: it left resting TREK-1 channels and channels opened by other activators untouched, and only prevented activation by arachidonic acid, probably by binding elsewhere on the channel. PE 22-28 has not been tested in that way. In a 2019 mouse stroke study the effect of mini-spadin was biphasic: at low concentrations it increased TREK-1 activity, at higher ones it blocked it.

The French group links the antidepressant-like effect to a rapid rise in BDNF, a growth factor for nerve cells, and to the formation of new neurons and synapses. The BDNF rise was measured for spadin only; for PE 22-28 the group showed more new cells in the mouse hippocampus and a rise in a synapse protein in cultured neurons. No pharmacokinetic study of PE 22-28 has been published, so its half-life in the blood and how much of it reaches the brain are unknown, in animals as well as in people.

Is PE-22-28 approved?

No. No medicine containing PE-22-28 or spadin is authorised in the EU, the Netherlands or the US. In the Netherlands it is not a registered medicine and may not be sold or promoted for human use; it circulates only as research material.

It has not entered clinical development either. ClinicalTrials.gov lists no trial of PE-22-28, mini-spadin or spadin (checked in October 2026). In a 2018 review the discovering group wrote that clinical trials of spadin or its analogues were 'currently in progress', but no such trial has appeared on ClinicalTrials.gov since.

In the United States it is not FDA-approved, and it does not appear in FDA's list of bulk substances nominated for use in pharmacy compounding (update of 14 May 2026).

In sport PE-22-28 is not named on the WADA Prohibited List, but as a pharmacological substance without approval for human use anywhere, it falls under category S0 and is prohibited at all times, in and out of competition. The Dopingautoriteit applies the same list in the Netherlands.

What the research shows

The PE-22-28 literature is small. Three papers test it for an effect, all from the Valbonne institute and its collaborators (2017, 2019 and 2021), and one 2026 paper from an independent laboratory used it as a tool to block TREK-1 in lung cells. All of it is in mice or cells, and none of the behavioural results has been repeated by another group. The main findings:

• Spadin, the parent (Mazella et al., PLoS Biol 2010): in five behavioural tests that predict antidepressant activity, mice given spadin resisted depression-like behaviour as mice without TREK-1 do, and four days of intravenous treatment increased CREB activation and the formation of new neurons in the hippocampus, markers that classical antidepressants raise only after weeks.
• PE 22-28 in depression tests (Djillani et al., Front Pharmacol 2017): in groups of 10 male mice, a single injection into the abdominal cavity cut the time spent motionless in the forced swim test, measured 30 minutes later, from about 162 to 92 seconds. Four days of treatment also worked in the learned helplessness test and, in mice made depression-like by seven weeks of corticosterone, in the forced swim and novelty-suppressed feeding tests, at a dose about 30 times lower than spadin's. It also worked when given by stomach tube.
• Same study, brain plasticity: four days of treatment nearly doubled the number of newly formed cells in the hippocampus (1,736 against 899 BrdU-labelled cells, five mice per group), and in cultured mouse cortical neurons the synapse protein PSD-95 kept rising for 36 hours, to about twice its level at 5 hours.
• Same study, duration: after one injection, the effect of the two modified versions (G/A-PE 22-28 and its biotin-tagged form) fell to half after 14 to 23 hours, depending on version and dose, against about 6 hours for spadin in earlier work. Unmodified PE 22-28 was not included in this time-course test, although the abstract reports the longer duration for PE 22-28 and its analogues together.
• Stroke (Pietri et al., Neuropharmacology 2019): in mice after an experimentally induced stroke (focal ischaemia), daily mini-spadin injections in the first week, then four days a week until the end of the study, prevented weight loss and the delayed loss of dopamine neurons, improved motor and cognitive recovery, prevented depression-like behaviour in the forced swim and novelty-suppressed feeding tests, and increased the formation of new neurons and synapses.
• Insulin-producing cells (Daziano et al., Pharmacol Res 2021): in laboratory experiments on pancreatic beta cells, the natural propeptide, spadin and mini-spadin protected the cells against death caused by the inflammatory signal interleukin-1β, and mini-spadin also stimulated beta-cell division.
• Lung cells (Majumder et al., Am J Physiol Lung Cell Mol Physiol 2026): a laboratory in Los Angeles used PE 22-28 to block TREK-1 in primary human lung-lining cells exposed to high oxygen and mechanical stretch. Blocking TREK-1 increased oxidative stress, caspase activation and inflammatory signals, as switching off the gene did, while two TREK-1 activators reduced signs of lung injury in mice. Here TREK-1 blockade was harmful rather than protective.
• Human data: none for PE 22-28 or spadin. The only human studies in this field measured the body's own sortilin propeptide in blood: levels were lower in people with major depression than in healthy controls, returned to normal in those who responded to antidepressants, and rose after successful electroconvulsive therapy. That makes the propeptide a candidate marker of depression, not evidence that PE 22-28 treats it.

PE-22-28 versus spadin

Spadin is the 17-amino-acid parent (propeptide positions 12 to 28); PE 22-28 is its last seven amino acids. In the same cell test PE 22-28 blocked TREK-1 at a concentration several hundred times lower (IC50 about 0.1 nM against about 40 nM), and in mice it worked at a dose about 30 times lower. Spadin's antidepressant-like effect wears off within about 6 to 7 hours of an injection; a longer effect has been shown for the modified versions of PE 22-28, not for PE 22-28 itself.

Spadin has the broader evidence base. Besides the original study there is a mouse study that looked for side effects and found no change in pain sensitivity, seizures, stroke damage, heart function, blood pressure or blood glucose, and an independent laboratory has examined how it acts on the channel. None of those checks has been done for PE 22-28, and no laboratory outside the original group has tested its antidepressant-like effect. Neither peptide has ever been given to people.

Safety: what is and is not known

Nothing is known about the effects of PE-22-28 in people. There are no human studies and no case reports in the medical literature, and no toxicity or pharmacokinetic study has been published even in animals. The only safety-related data are the 2017 cell tests, in which it left four related potassium channels and the hERG heart channel alone. The mouse experiments were short and were not designed to look for harm.

The biology gives reasons for caution. Mice without TREK-1 are more sensitive to pain, epileptic seizures and brain ischaemia; spadin did not cause these effects in mice, but PE 22-28 has not been tested for them. TREK-1 also plays a part in heart rhythm and in the lungs and blood vessels, and in stressed human lung cells, blocking it with PE 22-28 made inflammation worse. How a potent TREK-1 blocker behaves in these tissues over weeks is unknown.

Products sold as PE-22-28 are research chemicals, not medicines; their identity and purity rest on the batch's certificate of analysis.

Frequently asked questions

Is PE-22-28 legal in the Netherlands?

PE-22-28 is not a registered medicine in the Netherlands or anywhere else in the EU, so it may not be sold or promoted for human use, and there is no authorised product a doctor could prescribe. It circulates only as research material.

Has PE-22-28 been tested in humans?

No. No published or registered study has given PE-22-28, or its parent spadin, to people, and ClinicalTrials.gov lists no trial of either. The evidence consists of mouse behaviour tests and cell experiments. The nasal sprays and injections under the skin discussed online have not been studied at all: the mouse experiments used injections into the abdominal cavity and dosing by stomach tube.

What is the difference between PE-22-28 and spadin?

Spadin is a 17-amino-acid fragment of the sortilin propeptide; PE-22-28 is its last seven amino acids. In cell tests PE-22-28 blocked TREK-1 at a concentration several hundred times lower, and in mice it worked at a dose about 30 times lower. Spadin has more research behind it, including a mouse side-effect study and independent work on its mechanism. Neither has been tested in people.

Does PE-22-28 work faster than ordinary antidepressants?

In mice, four days of treatment produced effects that, according to the researchers, classical antidepressants such as fluoxetine need three to four weeks to reach. Whether that applies to people is unknown. The forced swim test and similar tests are screening tools for antidepressant-like activity in rodents; they do not show that a compound treats depression, and PE-22-28 has never been tested in anyone with depression.

Does PE-22-28 improve focus or memory?

There is no evidence for that. No study has tested PE-22-28 for focus or memory in healthy animals, and none in people. The only cognitive finding comes from mice recovering from an experimental stroke, which did better on motor and cognitive tests after mini-spadin. Claims that it works as a nootropic go well beyond the data.

Is PE-22-28 banned in sport?

Yes. It is not named on the WADA list, but as a pharmacological substance with no approval for human use anywhere, it falls under category S0 and is prohibited in and out of competition. The Dopingautoriteit applies the same list in the Netherlands.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.