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
This site does not publish doses, durations or frequencies for any compound. Published research protocols for this compound vary considerably between studies in design, intensity and duration. Those details are not something to copy from a fitness website — anyone researching this compound should read the primary literature directly and talk to a doctor who knows their bloods.
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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