Overview
PE-22-28 is a 7-amino-acid synthetic peptide derived from spadin, an endogenous fragment of the sortilin propeptide. It selectively blocks the TWIK-related potassium channel-1 (TREK-1), a two-pore-domain K+ channel that gates serotonergic neurotransmission. TREK-1 knockout mice display a depression-resistant phenotype, and pharmacologic TREK-1 blockade is being explored as a fast-acting antidepressant mechanism distinct from monoamine reuptake inhibition.
In preclinical rodent models—forced swim test, tail suspension, chronic mild stress—PE-22-28 produces antidepressant-like effects within 4 days of dosing, compared with 2–4 weeks for SSRIs. It also increases hippocampal BDNF, promotes adult neurogenesis in the dentate gyrus, and improves synaptic plasticity without the cardiac, gastrointestinal, or seizure-threshold liabilities historically associated with spadin.
PE-22-28 is not FDA-approved and has not entered human clinical trials. It is sold as a research peptide. All human use is experimental and off-label; pharmacokinetics, dosing, and safety in humans are unknown.
Quick facts
- Mechanism
- Selective TREK-1 potassium channel blocker derived from spadin
- Primary use
- Antidepressant and neurogenic research peptide
- Evidence
- preliminary
- FDA
- Not approved
- Route
- Subcutaneous or intranasal (research only)
- Typical results
- Reduces depression-like behavior in rodent models within days; no human efficacy data
Chemical information
PE-22-28 (C₂₂H₅₂N₁₀O₈) is a cognition compound with a molecular weight of 773.9 g/mol. Its structural characteristics underpin its biological activity in cognitive function and neural health.
How PE-22-28 works
PE-22-28 binds and inhibits TREK-1 channels expressed on serotonergic neurons in the dorsal raphe nucleus. TREK-1 blockade depolarizes these neurons, increasing firing rate and serotonin release in projection regions including the prefrontal cortex and hippocampus. Downstream, this drives BDNF expression and adult neurogenesis in the dentate gyrus—mechanisms strongly implicated in antidepressant response.
TREK-1 is a two-pore-domain K+ leak channel that hyperpolarizes neurons and limits firing. Genetic deletion of TREK-1 produces a depression-resistant phenotype with enhanced 5-HT neurotransmission, providing strong rationale for pharmacologic blockade.
Native spadin (44 amino acids) showed antidepressant activity in rodents but also affected cardiac TREK-1 and had a short half-life. PE-22-28 was developed as a shortened, more selective, and more stable analogue with preserved CNS efficacy and improved peripheral safety profile in animals.
Beyond the monoamine effect, PE-22-28 increases BDNF and adult neurogenesis—consistent with the 'neurogenic hypothesis' of antidepressant action—and may have neuroprotective effects in models of stroke and excitotoxicity.
- TREK-1 blockade: Inhibits leak K+ current, depolarizing serotonergic neurons
- 5-HT enhancement: Increases serotonin firing/release in cortex and hippocampus
- Fast onset: Antidepressant-like effects within ~4 days in rodents
- Neurogenesis: Increases BDNF and hippocampal neurogenesis
- Improved selectivity: Less cardiac TREK-1 activity than native spadin
Pharmacokinetics
| Parameter | Value | Significance |
|---|---|---|
| Molecular Mass | ~830 g/mol | Short 7-amino-acid peptide |
| Plasma half-life | Not characterized in humans | Limits dose translation |
| Oral bioavailability | Negligible (peptide degradation) | Requires SC or intranasal delivery |
| Intranasal CNS access | Possible based on size; unverified in humans | Theoretical advantage for CNS targets |
| Metabolism | Proteolytic degradation | No CYP interactions expected |
Dosing & administration
PE-22-28 dosing varies by indication and individual factors. No FDA-approved dosing exists for this compound; protocols in the literature derive from limited clinical or preclinical data and practitioner experience.
Any use should be conducted under qualified medical supervision with appropriate monitoring of safety markers.
Important: These dosing ranges are not FDA-approved. Any use should be under qualified medical supervision.
Side effects & safety
Safety data for PE-22-28 is primarily derived from preclinical studies and limited human data. Long-term effects in humans remain incompletely characterized.
Common
- • Not characterized in humans
- • Injection-site reactions reported anecdotally
- • Mild headache
- • Transient anxiety or agitation (mechanism-plausible)
Serious / potential risks
- • Unknown human safety profile
- • Potential serotonin syndrome with concomitant serotonergic drugs
- • Theoretical cardiac TREK-1 effects (reduced vs spadin but not eliminated)
- • Unknown long-term effects on neural stem cell pools
- • Quality and identity of research-chemical material is variable
Drug interactions
| Medication | Interaction | Recommendation |
|---|---|---|
| SSRIs/SNRIs | Theoretical additive serotonergic effect; risk of serotonin syndrome | Avoid combination without supervision |
| MAO inhibitors | High risk of serotonin syndrome | Contraindicated combination |
| Triptans, tramadol | Additive serotonergic risk | Avoid in research design |
| Antipsychotics | Unknown effects on TREK-1 and 5-HT signaling | No clinical data |
Storage & handling
Lyophilized (powder)
- • Store at -20°C to 4°C (freezer or refrigerator)
- • Protect from light and moisture
- • Stable for 12–24 months when stored properly
- • Keep in original sealed container until reconstitution
Reconstituted solution
- • Refrigerate at 2–8°C after reconstitution
- • Use bacteriostatic water for multi-dose reconstitution
- • Typical stability: 14–28 days refrigerated
- • Do not freeze reconstituted solution
Cost & availability
| Source | Cost | Notes |
|---|---|---|
| Research suppliers | Varies widely | Quality and purity vary significantly between sources |
| Compounding pharmacies | Prescription required | Higher quality assurance and purity testing |
The bottom line
PE-22-28 is a cognition compound with research interest in antidepressant, trek-1, cognition. While preclinical evidence is encouraging, it remains investigational and is not FDA-approved. Any use should be under qualified medical supervision.
Best for
- • Researchers studying cognitive function and neural health
- • Individuals interested in antidepressant under medical guidance
Not for
- • Self-administration without medical supervision
- • Pregnant or breastfeeding individuals
- • Individuals with contraindicated conditions
Related compounds
Frequently asked questions
References
- [1] Mazella J, Pétrault O, Lucas G, et al.. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol (2010). doi: 10.1371/journal.pbio.1000355 PMID: 20405029
- [2] Djillani A, Pietri M, Moreno S, et al.. Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity. Front Pharmacol (2017). doi: 10.3389/fphar.2017.00643 PMID: 28955238
- [3] Heurteaux C, Lucas G, Guy N, et al.. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci (2006). doi: 10.1038/nn1749 PMID: 16878133