PE 22-28 is a very short peptide (a chain of seven amino acids) designed in 2017 by a French team at the Institute of Molecular and Cellular Pharmacology near Nice. It was built as an improved version of an older compound called spadin. It has only one described job: to shut the TREK-1 potassium channel — a protein “valve” in the membrane of a nerve cell. In mice, closing that valve produced something resembling the effect of an antidepressant, but after four days rather than after three or four weeks. The most important thing has to be said straight away, though: everything known about PE 22-28 comes from cells in a dish and from mice. There is not a single human study, no data on absorption, breakdown or safety, and the TREK-1 channel itself has jobs in the body that can turn against us once it is blocked.
What PE 22-28 is
The name is simply the address of a fragment. It all started with a larger molecule abbreviated PE. Its slice from position 12 to 28 — seventeen amino acids — is spadin, the peptide described in 2010 as the first natural compound with antidepressant activity acting through the TREK-1 channel. PE 22-28 is an even shorter piece of the same sequence, from position 22 to 28, that is seven amino acids. The literature sometimes calls it “mini-spadin”.
Why shorten it at all? The researchers looked at the pieces spadin breaks down into inside mouse blood, and assembled a new, shorter peptide out of those breakdown products. The result beat the original on both counts — how hard it grips the channel, and how long it survives inside the animal.
Where it comes from — sortilin and spadin
Spadin is not a chemist's invention. It arises in the body during the “maturation” of a protein called sortilin (also known as NTSR3): when the cell trims that protein into its working form, the snipped-off piece is released outside. Mazella's team showed in 2010 that sortilin physically associates with the TREK-1 channel, and that the peptide cut from it binds this channel with an affinity of around 10 nanomoles — reasonably tight. That was the starting point of the whole family: a natural peptide the body makes itself turned out to block a channel tied to mood.
PE 22-28 is therefore a derivative of a derivative. That the molecule descends from a protein already present in the body is, however, no argument at all that giving it from outside is safe.
How it works — the TREK-1 channel put simply
Potassium channels are the valves through which potassium flows out of a nerve cell. The more of those valves stand open, the harder the cell is to excite — leaking potassium quietens it down. TREK-1 belongs to the “background” channels: it is partly open all the time and makes sure the cell does not fire at any little thing.
Blocking TREK-1 shuts some of those valves, so the cell becomes easier to excite. In the circuits that govern mood, particularly the serotonin system, this means stronger signalling. Hence the idea of using channel blockade as a completely different route to an antidepressant effect than the one classical drugs take: SSRIs raise serotonin levels between cells, a TREK-1 blocker changes the excitability of the cells themselves.
The strongest evidence that the direction is real does not come from peptides at all, but from mouse genetics. When the TREK-1 gene was switched off in mice in 2006, the animals behaved across five different tests the way animals given antidepressants behave, and their hormonal stress response (the corticosterone surge) was markedly blunted. That showed the channel genuinely takes part in regulating mood, rather than being an electrophysiological curiosity.
What was studied — cells and animals
The 2017 source paper gathered four kinds of result. First, electrophysiology: on the human TREK-1 channel expressed in cultured cells, PE 22-28 shut down the current at a concentration two to three orders of magnitude lower than spadin (the half-maximal inhibitory concentration was 0.12 nanomoles against 40-60 nanomoles for spadin). That comparison is the origin of the line repeated online about action “several hundred times stronger” — the figure is real, but it describes the grip on a channel in a dish, not any effect in a human being.
Second, mouse behaviour: in the forced swimming test the animals spent less time immobile, and in the novelty-suppressed feeding test, after a four-day course, they got down to eating sooner. Both tests are standard antidepressant signals in animal pharmacology.
Third, brain tissue: after four days the authors saw increased neurogenesis, that is the birth of new nerve cells, and in cultured mouse cortical neurons a rise in PSD-95, a protein taken as a marker of new connections forming. Classical antidepressants need three to four weeks to produce such changes. Fourth, durability: spadin's action in mice faded after roughly seven hours, whereas for PE 22-28 and its derivatives the authors report the effect lasting up to about 23 hours — and that was the main reason for shortening the molecule.
Stroke is a separate thread. In 2019 the same team gave mini-spadin to mice with focal brain ischaemia and reported a result worth remembering: the action turned out to be biphasic. At very small amounts the peptide opened the TREK-1 channel and protected the tissue; at larger ones it closed the channel and produced the antidepressant effect. The animals had smaller motor and cognitive deficits and milder post-stroke depression. Biphasic behaviour means, though, that the direction of the effect depends on how much compound is present — the hardest kind of pharmacology to predict.
No human studies — what that means
Searching PubMed under “PE 22-28”, “spadin” and “TREK-1” returns preclinical work only. The ClinicalTrials.gov registry lists no trial of PE 22-28, of spadin, or of any other TREK-1 blocker as an investigational drug. So it is not that human testing went badly — it never started. Even the parent compound, described since 2010 as a “promising candidate”, has not entered clinical development fifteen years later.
For PE 22-28, then, nothing is known about the things that decide safety: how much reaches a human brain, how fast it breaks down, what adverse effects it has, how it interacts with medicines. The “protocols” circulating online are conversions of amounts injected into the abdominal cavity of mice, and a mouse-to-human conversion is arithmetic, not data.
The other side of TREK-1 — why blocking it may do harm
This is the part missing from promotional material. TREK-1 is not a “mood channel”: it sits throughout the central nervous system, and also in the heart, smooth muscle, the pancreas and the prostate, everywhere keeping cells below the firing threshold.
In 2004 the same centre showed the flip side in mice lacking the TREK-1 gene: those animals were more vulnerable to epilepsy and to ischaemia of the brain and spinal cord, and the protective action of polyunsaturated fatty acids, striking in normal mice, disappeared in them. The very absence of TREK-1 that guards against depression thus strips nervous tissue of a natural safety buffer. Chronic pharmacological closure of the channel recreates exactly that state, so a theoretical seizure risk and poorer brain tolerance of low oxygen are not scaremongering — they follow directly from the model the whole concept rests on. The same paper also showed that mice without TREK-1 are harder to anaesthetise with inhaled general anaesthetics.
Safety and the limits of the evidence
Beyond the absence of human data, two further limitations belong here. The first: practically the entire literature on spadin and its shortened analogues comes from one laboratory — the Borsotto, Mazella and Heurteaux group at the CNRS in Valbonne. No independent centre has replicated the findings, and that is the basic filter against chance results.
The second: classical antidepressants, fluoxetine included, also inhibit the TREK-1 channel. That means an overlapping target and entirely unstudied consequences of combining them. It is also unknown whether PE 22-28 given by any route other than intraperitoneal injection in mice reaches the brain at all — the intranasal route talked about online has never been tested for this peptide. We deliberately give no methods of use and no doses.
The wider context — peptides acting on the brain
PE 22-28 is an extreme case of something common in this category: an elegant mechanism, good rodent results, and zero translation into the clinic. It is worth setting against peptides that have at least some human data — Selank and Semax, say, where the literature is admittedly concentrated in one country but does include studies involving people.
Summary
PE 22-28 is a seven-amino-acid abbreviation of spadin, designed to block the TREK-1 potassium channel harder and for longer. In cells it inhibits that channel several hundred times more potently than the parent compound; in mice it gives an antidepressant signal after four days and drives the birth of new neurons. That is where the facts end. There are no human studies, no data on what the compound does inside a human body, and the mechanism has a documented dark side: animals lacking TREK-1 are more prone to seizures and tolerate brain ischaemia less well. The state of the evidence for PE 22-28 should be described as early preclinical, from a single centre and without independent replication.
Sources
- Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. Frontiers in Pharmacology. 2017;8:643. PMID: 28955242. DOI: 10.3389/fphar.2017.00643. pubmed.ncbi.nlm.nih.gov/28955242
- Mazella J, Petrault O, Lucas G, et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biology. 2010;8(4):e1000355. PMID: 20405001. DOI: 10.1371/journal.pbio.1000355. pubmed.ncbi.nlm.nih.gov/20405001
- Heurteaux C, Lucas G, Guy N, et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nature Neuroscience. 2006;9(9):1134–1141. PMID: 16906152. DOI: 10.1038/nn1749. pubmed.ncbi.nlm.nih.gov/16906152
- Heurteaux C, Guy N, Laigle C, et al. TREK-1, a K+ channel involved in neuroprotection and general anesthesia. The EMBO Journal. 2004;23(13):2684–2695. PMID: 15175651. DOI: 10.1038/sj.emboj.7600234. pubmed.ncbi.nlm.nih.gov/15175651
- Pietri M, Djillani A, Mazella J, Borsotto M, Heurteaux C First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. Neuropharmacology. 2019;158:107715. PMID: 31325429. DOI: 10.1016/j.neuropharm.2019.107715. pubmed.ncbi.nlm.nih.gov/31325429
- Djillani A, Pietri M, Mazella J, Heurteaux C, Borsotto M Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacology & Therapeutics. 2019;194:185–198. PMID: 30291907. DOI: 10.1016/j.pharmthera.2018.10.003. pubmed.ncbi.nlm.nih.gov/30291907
- Djillani A, Mazella J, Heurteaux C, Borsotto M Role of TREK-1 in Health and Disease, Focus on the Central Nervous System. Frontiers in Pharmacology. 2019;10:379. PMID: 31031627. DOI: 10.3389/fphar.2019.00379. pubmed.ncbi.nlm.nih.gov/31031627
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.