PE-22-28: Research Overview

PE-22-28 is a synthetic 7-amino-acid peptide derived from spadin, itself a fragment of the sortilin propeptide. Designed by researchers at the Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) in Valbonne, France, PE-22-28 was engineered from a systematic study of spadin's blood-degradation products to identify the shortest sequence retaining potent TREK-1 channel antagonism. Preclinical work, conducted primarily in the Borsotto and Heurteaux laboratory, demonstrates antidepressant-like behavioral effects in rodents after acute administration — a profile that distinguishes it from conventional monoamine-based antidepressants that require weeks of dosing. No human trials exist.

What Is PE-22-28?

PE-22-28 refers to residues 22 through 28 of the 33-amino-acid spadin peptide (Ser-Arg-Arg-His-Thr-Ser-Glu). Spadin was originally identified as a cleaved propeptide of sortilin — a type-I transmembrane receptor — and was shown to act as an endogenous antagonist of TREK-1 (TWIK-related potassium channel 1), a two-pore domain background potassium channel. PE-22-28 was identified as the minimal pharmacophore: a linear heptapeptide with nanomolar affinity for TREK-1 and improved in vivo half-life compared to full-length spadin. The molecular weight is approximately 870 Da. It is sold by research-chemical vendors in lyophilized form and is not approved by any regulatory authority for human use.

Mechanism

TREK-1 is a two-pore domain potassium channel that sets resting membrane potential in neurons and modulates serotonergic neurotransmission. Genetic knockout of TREK-1 in mice produces a depression-resistant phenotype with increased serotonin availability — the channel is regarded as a negative regulator of monoamine tone. PE-22-28 blocks TREK-1 with an IC50 of approximately 0.12 nM in vitro, markedly more potent than spadin's IC50 of 40–60 nM. This pharmacological blockade is proposed to increase neuronal excitability in serotonergic circuits and, separately, to stimulate hippocampal neurogenesis — an increase in PSD-95 (a postsynaptic density marker of synaptogenesis) was reported in parallel with behavioral antidepressant effects. PE-22-28 is thought to bind an extracellular domain of TREK-1 without entering the cell.

What the Research Shows

Published research is preclinical only — no human clinical trials have been conducted. The pivotal study by Djillani, Pietri, Moreno, Heurteaux, Mazella, and Borsotto (2017, PMID 28955242) characterized PE-22-28 and related shortened spadin analogs in rodent forced-swim and tail-suspension tests — two established behavioral models of antidepressant activity. PE-22-28 reduced immobility times after acute intraperitoneal, intravenous, and oral (gavage) administration, suggesting oral bioavailability may be viable in rodents. In vivo half-life was estimated at approximately 7 hours, extended further by modified analogs. The same study reported increased hippocampal PSD-95 expression, consistent with synaptogenic effects. An earlier 2014 study by Moha Ou Maati et al. (PMID 25080852) characterized retroinverso analogs of spadin with similar antidepressant profiles, providing structural context for the PE-22-28 series. A 2019 review in Pharmacology & Therapeutics (PMID 30291907) by Heurteaux and colleagues summarized the TREK-1-targeted antidepressant strategy, positioning PE-22-28 as the leading analog. All reported research originates from the IPMC group in France; no independent replication has been published.

Reported Research Dose Ranges

Not medical advice. These are ranges reported in research literature, not personalized recommendations. Consult your physician.

Preclinical rodent doses cannot be directly translated to humans; published human dose-finding studies do not exist. In published rodent studies, PE-22-28 was administered at doses in the range of 1–10 mg/kg via intraperitoneal or intravenous routes, with a single acute dose sufficient to produce behavioral effects in forced-swim and tail-suspension paradigms. Oral administration (gavage) was also tested at similar weight-based ranges. No safety, tolerability, or pharmacokinetic data exist in humans, and no regulatory body has established an acceptable human dose.

References

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.

2. Moha Ou Maati H, Borsotto M, Chatelain F, Widmann C, Lazdunski M, Heurteaux C. Activation of ATP-sensitive potassium channels as an element of the neuroprotective effects of the traditional Chinese medicine MLC901 against oxygen glucose deprivation. Neuropharmacology. 2014; and: Retroinverso analogs of spadin display increased antidepressant effects. PMID 25080852.

3. Heurteaux C et al. Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. Pharmacol Ther. 2019;194:185-198. PMID 30291907.

4. 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.