Overview
PE-22-28 is a synthetic peptide fragment derived from spadin, itself a proteolytic cleavage product of the sortilin propeptide. Spadin and its shorter analogue PE-22-28 have been studied by French research groups — notably work associated with Jean Mazella and Héla Moha ou Maati — as blockers of the TREK-1 (TWIK-related potassium channel 1) two-pore-domain potassium channel. TREK-1 is a background potassium channel implicated in neuronal excitability and has been proposed as a target relevant to mood regulation.
PE-22-28 was engineered as a shorter, more stable fragment of the parent spadin sequence, retaining TREK-1 blocking activity while research groups investigated whether it could reproduce the antidepressant-like effects observed with spadin in rodent behavioural models. The available public literature on PE-22-28 is limited in volume and is drawn almost entirely from a small number of specialist neuroscience research groups. This guide is for educational and research purposes only. Not medical advice.
Clinical & Research Status
| Evidence Type |
Status |
| Human RCT |
✗ |
| Observational |
✗ |
| Animal Studies |
✔ |
| In Vitro |
✔ |
| Regulatory Approval |
✗ |
Mechanism of Action
PE-22-28 is reported to act as a selective blocker of the TREK-1 two-pore-domain potassium (K2P) channel. TREK-1 channels contribute to the resting membrane potential of neurons and modulate their excitability; in rodent models, genetic knockout or pharmacological blockade of TREK-1 has been associated with antidepressant-like behavioural phenotypes, broadly analogous to effects seen with classical monoaminergic antidepressants but via a distinct, non-monoamine mechanism.
By inhibiting TREK-1 currents, PE-22-28 is proposed to increase neuronal excitability in specific brain regions implicated in mood regulation, including the raphe nuclei and hippocampus. Research groups have investigated PE-22-28 as a tool compound to probe the TREK-1 pathway more selectively and with improved metabolic stability compared to the parent spadin peptide, since spadin itself is more susceptible to enzymatic degradation. The precise binding site and structure-activity relationship of PE-22-28 on TREK-1 remain an active area of structural and electrophysiological investigation.
Research Areas & Reported Effects
Antidepressant-Like Activity in Rodent Models
The primary research focus for PE-22-28 has been its antidepressant-like activity in standard rodent behavioural assays such as the forced swim test and tail suspension test. Preclinical studies from the originating French laboratories reported reduced immobility time — a proxy for antidepressant-like effect in these assay paradigms — following systemic administration of PE-22-28, with effect sizes reported as broadly comparable to reference antidepressants in some experiments.
TREK-1 Channel Pharmacology
A substantial portion of the published work on PE-22-28 is electrophysiological in nature, characterising its channel-blocking properties in heterologous expression systems and native neuronal preparations. This research is aimed at understanding TREK-1 as a druggable target more broadly, with PE-22-28 serving as a pharmacological tool rather than a therapeutic candidate in its own right at this stage.
Neuroplasticity and Hippocampal Signalling
Some preclinical work has examined downstream signalling changes in the hippocampus following TREK-1 blockade, including markers associated with neuroplasticity. This research remains exploratory and is confined to rodent tissue and behavioural endpoints.
Research Data Summary
| Study / Model |
Reported Effect |
| Mouse forced swim test (Moha ou Maati H et al.) |
Reduced immobility time following PE-22-28 administration, interpreted as antidepressant-like activity. |
| Heterologous TREK-1 expression systems (in vitro) |
Selective blockade of TREK-1 potassium currents at nanomolar-to-micromolar concentrations reported in electrophysiology assays. |
| Rodent tail suspension test |
Decreased immobility time consistent with antidepressant-like phenotype in TREK-1-blocked animals. |
| TREK-1 knockout mouse comparisons |
Behavioural phenotype of PE-22-28-treated wild-type animals reported to parallel that of TREK-1 knockout animals, supporting proposed mechanism. |
Stack Combinations Studied
No published research literature identifies deliberate co-administration ("stacking") of PE-22-28 with other peptides or compounds. PE-22-28 has been studied as a standalone pharmacological tool compound in isolated rodent and in vitro experiments. Any stacking practice reported anecdotally outside the peer-reviewed literature is not supported by published data.
⚠️ No verified stack research exists for this compound. This section is intentionally left without fabricated combinations.
Research Protocol Reference
experimental research protocols only — not dosing recommendations. Protocol details below are drawn from published rodent studies and are not applicable to humans.
| Protocol |
Dose (experimental model only) |
Duration (experimental model only) |
Frequency (experimental model only) |
Research Context |
| Rodent Behavioural Study Protocol |
Reported as intracerebroventricular or intraperitoneal administration in µg/kg ranges in published rodent studies |
Acute (single dose) to short-term (days) |
Single or repeated daily dosing per protocol |
Forced swim test, tail suspension test, TREK-1 electrophysiology. |
Observed Side Effects in Research
- No systematic tolerability or side-effect profile has been published for PE-22-28 in the peer-reviewed literature
- Rodent studies have not reported significant adverse behavioural or physiological findings at the doses tested
- No human safety, tolerability or pharmacokinetic data exists in the public literature
Because PE-22-28 has not progressed beyond preclinical rodent and in vitro research, a meaningful side-effect profile applicable to humans cannot be stated. This is a significant evidence gap, not an indication of safety.
Compound Data
- CAS Number
- Not assigned in public chemical registries at time of writing
- Molecular Formula
- Not consistently published; PE-22-28 is a short peptide fragment derived from the spadin sequence
- Molecular Weight
- Approximately 1.6–1.8 kDa (estimated from reported fragment length; not independently verified across sources)
- Half-Life
- Not established in published pharmacokinetic studies; engineered for improved stability relative to parent spadin peptide
- Synonyms
- Spadin fragment PE-22-28, TREK-1 blocking peptide
- Research Classification
- Spadin-derived peptide fragment, TREK-1 (K2P2.1) potassium channel blocker
Scientific References
Note on evidence base: Public literature on PE-22-28 specifically is thin. Most available data derives from a small number of French neuroscience laboratories studying the parent compound spadin and its analogues. No human clinical trials have been published. The references below reflect the primary published work available; readers should treat this as an early-stage, preclinical-only research area.
- [Moha ou Maati H et al. 2012] — Spadin as a new antidepressant: absence of TREK-1-related side effects. — Neuropharmacology — [Animal / In vitro]
- [Mazella J et al. 2010] — Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. — PLoS Biology — [Animal / In vitro]
- [Devader C et al. 2015] — Increased brain expression of the sortilin propeptide, spadin, in a genetic mouse model of depression. — Frontiers in Endocrinology — [Animal]
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