PE-22-28 Research

PE-22-28 is a seven-residue peptide derived from spadin, designed to block the TREK-1 potassium channel and studied for antidepressant-like effects in mice. PE-22-28 research is small in volume, entirely preclinical, and concentrated in a single laboratory.

What PE-22-28 is

PE-22-28 is a heptapeptide corresponding to residues 22 to 28 of the sortilin/NTSR3 propeptide, known in this literature as PE. Its CAS number is 1801959-12-5 and its molecular weight is 773.9 g/mol.

The compound also appears in this literature under the alias mini-spadin, and the two names denote the same molecule. Mazella 2018 defines the sequence 22 to 28 as mini-spadin, citing the paper that introduced it ^[4].

Spadin is a different molecule, PE 12-28, a seventeen-residue peptide and the parent compound. The spadin literature runs to roughly eighty PubMed records, and the large majority of them are about spadin rather than about PE-22-28. Two of those records carry genuine PE-22-28 data under the mini-spadin alias, and neither abstract writes the name PE-22-28 ^[2][3].

The TREK-1 rationale

The rationale predates the peptide by eleven years. Deleting the TREK-1 gene in mice produced a depression-resistant phenotype across several behavioral models ^[7]. That is a mouse genetic result about the channel, not about any peptide. Spadin followed, and the paper introducing it describes its target as rodent TREK-1 channels ^[8].

One review from the originating group notes that fluoxetine blocks TREK-1 and has proven clinical efficacy in depression ^[5]. Fluoxetine's clinical effect is attributed to serotonin reuptake inhibition, so reading it as validation of TREK-1 blockade is circular.

What the founding study reported

Djillani 2017 is the single primary paper naming PE-22-28, and it identified the peptide from spadin's own degradation products in blood ^[1].

In vitro, using patch clamp on human TREK-1 in HEK cells, PE-22-28 inhibited the channel at sub-nanomolar concentration. That paper's own measurement for spadin is 40 nM, and it separately quotes a 40 to 60 nM range for spadin from earlier work. It claims more than a three-hundred-fold improvement over spadin. A later review from the same group gives a range of forty to three hundred and fifty times ^[4]. That review applies the range to the analog set rather than to PE-22-28 alone. The paper quotes two slightly different sub-nanomolar values for PE-22-28 in different sections.

In mice, PE-22-28 reduced forced-swim immobility after acute treatment, novelty-suppressed feeding latency after four days, and immobility again in a corticosterone-induced model. In that corticosterone arm the paper used PE-22-28 as the representative peptide for the spadin-analog set ^[1]. The paper also reported reduced escape latencies in a mouse learned helplessness test, run on the analog set rather than on PE-22-28 alone ^[1]. Every behavioral arm used ten mice per group, all naive male C57Bl/6J, and no female animals were used in that study.

The behavioral evidence in that study is entirely screening-assay evidence in mice. The forced swim test, novelty-suppressed feeding and learned helplessness are compound-detection assays with a long record of flagging molecules that later fail in humans. The corticosterone model is a chemically induced surrogate in animals rather than a disease model. The antidepressant case for PE-22-28 rests on mouse assays of that kind, in the founding study and in the stroke study alike.

The study also reported more newborn hippocampal cells in mice, and raised PSD-95 in cultured mouse cortical neurons in vitro. The paper states the prominent neurogenesis effect belonged to a modified derivative rather than to plain PE-22-28.

The internal result that undercuts the mechanism

Table 1 of that same paper separates the behavior from the stated mechanism. Two fragments, PE 22-25 and PE 14-25, did not significantly inhibit TREK-1 yet both still significantly reduced forced-swim immobility in mice. PE 14-25 produced a small current increase rather than a block. A third fragment, PE 12-27, was active in both assays, and only PE 22-27 was inactive in both.

So peptides that do not block TREK-1 produced an antidepressant-like effect of similar magnitude, in the same assay and the same table. This is an in vitro and mouse comparison, not a human one. It weakens the attribution of the behavioral result to TREK-1 blockade.

Duration and derivative attribution

The paper's duration figures do not belong to PE-22-28. The half-effect times of fourteen to twenty-three hours were measured in mice on two modified derivatives, G/A-PE 22-28 and its biotinylated form. Plain PE-22-28 was not in that experiment and has no published duration-of-action figure at all.

The paper's abstract attributes the duration improvement to PE-22-28 and its analogs together, while its results section names only the two derivatives.

No pharmacokinetics, bioavailability or brain-penetration measurement has been published for PE-22-28. The founding paper also reports activity in the mouse forced swim test after oral gavage. That required a far larger amount than the injected route, which is what poor oral absorption of a heptapeptide would predict.

The two later studies

Pietri 2019 is the only other in vivo study, and in a mouse focal-ischemia model it reported a biphasic action on TREK-1 under the mini-spadin name ^[2]. At a low dose the channel was activated, and at a roughly hundred-fold higher dose it was inhibited. The peptide also reduced ischemia-induced motor, cognitive and depression-like deficits in those mice. That paper's abstract does not state group sizes.

Daziano 2021 is cell-culture work, published under the same mini-spadin alias ^[3]. In vitro, PE, spadin and mini-spadin protected pancreatic beta cells from interleukin-1-beta-induced death, and mini-spadin also promoted beta-cell proliferation. That is an off-target signal rather than antidepressant evidence.

Human research and regulatory status

No published human study of PE-22-28 exists under either of its names, and ClinicalTrials.gov lists no study of it. The parent compound spadin has no study in that registry either, sixteen years after its introduction.

The nearest human signal attaches to the target gene rather than to the molecule. A pharmacogenetic analysis inside a human clinical trial linked KCNK2/TREK1 variants to non-remission on citalopram ^[10]. That is a candidate-gene association from a class of findings that has replicated poorly, and it is not human evidence for PE-22-28.

PE-22-28 holds no United States drug approval. Its absence from that record is the absence of a compound never filed, rather than one withdrawn or refused. United States drug label and approval records list nothing for PE-22-28, mini-spadin or spadin.

Safety data

No safety pharmacology of any kind has been published on PE-22-28. The study routinely attached to it tested spadin instead, a structurally different and far weaker peptide ^[9]. It reported an absence of TREK-1-related effects on cardiac function, pain and glucose homeostasis in rodents, and those are spadin's results.

That study exists because its authors state TREK-1 deletion increases sensitivity to pain, seizures and ischemia ^[9]. It also tested seizures and ischemia, the two other domains named in that premise. In those rodents spadin did not change infarct size after focal ischemia, and kainate-induced seizures were unchanged ^[9]. Both were null results rather than positive safety findings, and both were measured on spadin.

In rodents, a selective TREK-1 activator was analgesic and spadin abolished that analgesia, so blocking the channel points away from pain relief ^[11].

A separate mouse study points the other way for stroke. Its authors record that the ischemia literature is split. Earlier work showed a neuroprotective role for TREK-1 in global cerebral and spinal cord ischemia, and its role in focal cerebral ischemia has long been debated ^[12]. In that mouse focal-ischemia work, TREK-1-deficient mice showed less neuronal death, smaller infarcts and milder blood-brain barrier breakdown ^[12]. Pharmacological inhibition of TREK-1 also reduced infarct size in that model, which is consistent with a blocker rather than a warning about one. The biphasic reversal reported in mice complicates any single reading of these signals ^[2].

Independence, replication and conflicts of interest

All three papers containing PE-22-28 data are led from one institute, IPMC/CNRS UMR7275 at Universite Cote d'Azur. Every author of the founding study and of the stroke study is based there. Seven of the beta-cell paper's eight authors are based there, and the eighth is at Universite Lille ^[3]. The same overlapping author core produced the target-validation knockout ^[7], the spadin discovery ^[8], the spadin safety study ^[9] and the group's reviews ^[4][5][6]. Rationale, molecule, safety data and secondary literature all trace to one laboratory.

Nine years on, no independent group has replicated the antidepressant-like finding, and none of the thirty papers citing the founding study is a replication. Two reviews from unrelated groups do discuss mini-spadin, and neither contains new data on it ^[13][14].

The founding paper declares no commercial or financial relationship, and declares public French funding with no pharmaceutical sponsor ^[1]. A declaration of absence is not independent confirmation. None of the three PE-22-28 papers carries a retraction, correction or erratum.

Development appears to have stopped, since the last publication with new PE-22-28 in vivo data is from 2019 and the last with any PE-22-28 data is from 2021.

Conclusion

PE-22-28 has a clear design rationale and a very thin evidence base. Its record is one primary study plus two papers under an alias, all preclinical and all centred on one laboratory. The founding paper's own table shows the behavioral effect separating from the stated mechanism. Nothing has been replicated independently, and nothing has been tested in people.

Frequently Asked Questions

Has PE-22-28 been studied in humans?

No published human study of PE-22-28 exists under either of its names, and ClinicalTrials.gov lists no study of it. The parent compound spadin has not reached a trial in that registry either.

Is mini-spadin the same compound as PE-22-28?

Yes. Mazella 2018 defines the sequence 22 to 28 as mini-spadin, citing the paper that introduced it ^[4]. The only other in vivo study ^[2] and the beta-cell study ^[3] both use that alias.

Is spadin research evidence about PE-22-28?

Studies of spadin itself are not. Spadin is PE 12-28, a seventeen-residue peptide with roughly eighty PubMed records of its own, and the safety study routinely attached to PE-22-28 tested spadin ^[9]. Two of those records carry genuine PE-22-28 data under the mini-spadin alias ^[2][3].

Has the antidepressant-like finding been replicated independently?

No. The founding study has been cited thirty times, and none of those citing papers is a replication. Two reviews from unrelated groups discuss mini-spadin, and neither contains new data on it ^[13][14].

References

1. 1

   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. Front Pharmacol. 2017;8:643. PMID 28955242. DOI: 10.3389/fphar.2017.00643
2. 2

   Pietri M, et al. 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
3. 3

   Daziano G, et al. Sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling pathway. Pharmacol Res. 2021;167:105539. PMID 33737242. DOI: 10.1016/j.phrs.2021.105539
4. 4

   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. PMID 30670975. DOI: 10.3389/fphar.2018.01541
5. 5

   Djillani A, Mazella J, Heurteaux C, Borsotto M. Fighting against depression with TREK-1 blockers: past and future. A focus on spadin. Pharmacol Ther. 2019;194:185-198. PMID 30291907. DOI: 10.1016/j.pharmthera.2018.10.003
6. 6

   Djillani A, Mazella J, Heurteaux C, Borsotto M. Role of TREK-1 in health and disease, focus on the central nervous system. Front Pharmacol. 2019;10:379. PMID 31031627. DOI: 10.3389/fphar.2019.00379
7. 7

   Heurteaux C, et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci. 2006;9(9):1134-1141. PMID 16906152. DOI: 10.1038/nn1749
8. 8

   Mazella J, et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol. 2010;8(4):e1000355. PMID 20405001. DOI: 10.1371/journal.pbio.1000355
9. 9

   Moha Ou Maati H, et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology. 2012;62(1):278-288. PMID 21807005. DOI: 10.1016/j.neuropharm.2011.07.019
10. 10

    Perlis RH, et al. Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR*D study. Neuropsychopharmacology. 2008;33(12):2810-2819. PMID 18288090. DOI: 10.1038/npp.2008.6
11. 11

    Busserolles J, et al. TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects. Br J Pharmacol. 2020;177(20):4782-4795. PMID 32851651. DOI: 10.1111/bph.15243
12. 12

    Zheng X, et al. The two-pore domain potassium channel TREK-1 promotes blood-brain barrier breakdown and exacerbates neuronal death after focal cerebral ischemia in mice. Mol Neurobiol. 2022;59(4):2305-2327. PMID 35067892. DOI: 10.1007/s12035-021-02702-5
13. 13

    Hu G, et al. Potential of heterogeneous compounds as antidepressants: a narrative review. Int J Mol Sci. 2022;23(22):13776. PMID 36430254. DOI: 10.3390/ijms232213776
14. 14

    Chen M, et al. TREK-1 in central nervous system diseases. Chin Med J (Engl). 2026;139(4):620-622. PMID 40539288. DOI: 10.1097/CM9.0000000000003662