# PE-22-28 — Research Peptide Profile

> PE-22-28 (mini-spadin) blocks the TREK-1 channel at 0.12 nM and showed rapid antidepressant-like effects within 4 days in mice. Evidence and limits.

Source: https://peptpedia.org/peptide/pe-22-28 | Published: 2026-09-18 | Last updated: 2026-09-18

PE-22-28, also called mini-spadin, is a 7-amino-acid fragment (Gly-Val-Ser-Trp-Gly-Leu-Arg) of the sortilin-derived antidepressant peptide spadin. It blocks the TREK-1 potassium channel with an IC50 of 0.12 nM, about 300 times more potent than spadin, and stays active up to 23 hours in mice versus 7 hours for spadin. Four-day treatment produced antidepressant-like behavior and hippocampal neurogenesis in rodents. No human studies have been published.

## Overview

PE-22-28 is the minimal active fragment of spadin, an endogenous 17-amino-acid peptide released from the propeptide of sortilin (neurotensin receptor-3) during its maturation. Spadin was identified in 2010 by Mazella and colleagues at the Institut de Pharmacologie Moleculaire et Cellulaire (CNRS, Universite Cote d'Azur) as the first peptidic blocker of TREK-1, a two-pore-domain potassium channel whose knockout produces a depression-resistant phenotype in mice. By analyzing spadin's blood degradation products, the same group designed PE 22-28 (positions 22-28 of the propeptide, sequence Gly-Val-Ser-Trp-Gly-Leu-Arg), a 7-residue analog that inhibited TREK-1 with an IC50 of 0.12 nM in patch-clamp assays, versus 40 nM for spadin, and remained active in vivo for up to 23 hours versus about 7 hours for the parent (PMID: 28955242). In mouse depression models it reduced immobility in the forced swim test after acute and 4-day sub-chronic dosing, was active orally, and roughly doubled hippocampal BrdU-positive newborn cells after 4 days. A later study found a biphasic dose response, with very low doses activating rather than blocking TREK-1 and protecting against ischemic injury and post-stroke depression. All evidence is preclinical; the only human data is an observational finding that serum levels of the endogenous parent propeptide rise after successful electroconvulsive therapy.

## Molecular Profile

- **Category:** cognitive-enhancement
- **Molecular formula:** C35H55N11O9
- **Molecular weight:** 773.9 g/mol
- **CAS number:** 1801959-12-5
- **Amino acid sequence:** Gly-Val-Ser-Trp-Gly-Leu-Arg
- **Also known as:** PE 22-28, Mini-Spadin, GVSWGLR, Spadin Analog PE22-28
- **Half-life:** Behavioral action up to about 23 hours in mice, versus about 7 hours for spadin; no plasma half-life published
- **Solubility:** Soluble in aqueous vehicles as used in the published studies (saline stocks)
- **Storage:** No validated stability data; lyophilized peptides of this class are typically stored at -20°C.

## Mechanism of Action

TREK-1 (KCNK2) is a background two-pore-domain potassium channel highly expressed in prefrontal cortex, hippocampus, and dorsal raphe. Blocking it increases neuronal excitability, and in dorsal raphe it raises serotonergic firing, the same downstream lever as SSRIs but reached directly rather than through transporter inhibition, which is why antidepressant-like effects appear within 4 days in mice instead of weeks (PMID: 20405001, 28955242). PE-22-28 binds the channel with sub-nanomolar affinity and showed no inhibition of related K2P channels TREK-2, TRAAK, TRESK, or TASK-1 in patch-clamp testing (PMID: 28955242). Mechanistically, spadin-family peptides selectively antagonize arachidonic-acid-mediated activation of TREK-1 through an allosteric mechanism (PMID: 32317978). Downstream, 4-day treatment increased hippocampal BrdU-positive cell counts (the study's neurogenesis readout) and raised PSD-95 expression on cortical neurons, a synaptogenesis marker (PMID: 28955242). At very low doses the same peptide activates TREK-1 and is neuroprotective, a biphasic pharmacology demonstrated in a focal-ischemia model (PMID: 31325429).

## Key Research Findings

- PE-22-28 (Gly-Val-Ser-Trp-Gly-Leu-Arg) is the minimal active fragment of spadin, designed from spadin's own serum degradation products; verified identity C35H55N11O9, 773.9 g/mol.
- It blocks the TREK-1 potassium channel at IC50 0.12 nM (about 300x spadin) with no activity at TREK-2, TRAAK, TRESK, or TASK-1, and lasts about 23 hours in mice versus 7 for spadin.
- Four-day treatment produced antidepressant-like behavior and near-doubled hippocampal neurogenesis in mice, with oral activity at 1 mg/kg.
- The pharmacology is biphasic (very low doses activate TREK-1 and are neuroprotective), and no human study exists; vendor dosing is extrapolated from microgram-per-kilogram mouse protocols.

## PE-22-28 Pharmacokinetics: Engineered From Spadin's Degradation Products

PE-22-28 exists because its developers mapped how spadin disappears from blood and kept the piece that survived. Its published pharmacokinetic facts are comparative and rodent-based: longer in vivo action than spadin, oral activity, and a biphasic dose response.

### From Spadin's Short Half-Life to a 23-Hour Fragment

- Spadin's antidepressant activity disappeared about 7 hours after administration in mice; HPLC and mass spectrometry of serum degradation identified stable fragments, leading to the design of PE 22-28 (PMID: 28955242).
- PE-22-28 and its active analogs remained behaviorally active up to 23 hours after administration, a roughly threefold duration improvement over spadin in the same forced-swim paradigm (PMID: 28955242).
- No formal half-life, clearance, or bioavailability number has been published for PE-22-28 in any species; the 7-hour and 23-hour figures are durations of behavioral effect, not plasma measurements.

### Routes and the Biphasic Dose Response

- Antidepressant-like activity was demonstrated after intraperitoneal injection at 3-4 mcg/kg and after oral gavage at 1 mg/kg in mice, the latter implying meaningful gut stability for a 7-residue peptide (PMID: 28955242).
- The dose-response is biphasic: 0.03 mcg/kg increased TREK-1 activity and was used as a neuroprotective regimen after focal ischemia, while 3 mcg/kg blocked the channel for antidepressant-like effects (PMID: 31325429).
- The G/A-substituted analog (glycine-22 to alanine, sequence AVSWGLR) showed equal or better activity (IC50 0.10 nM) and the strongest neurogenesis signal, and retroinverso chemistry extended duration further in related analogs (PMID: 28955242, 25080852).

## Safety & Tolerability

PE-22-28 is preclinical only, but its characterization is unusually thorough for a research peptide: defined sub-nanomolar target, selectivity shown against related potassium channels, and rodent studies reporting no locomotor, pain, or seizure-type liabilities for the family. The biphasic dose response, where very low doses produce the opposite channel action, is the most concrete safety-relevant finding. No human exposure data exists.

**Human data status:** No human trials or human dosing data. The only human evidence is observational: endogenous sortilin propeptide (spadin's parent) was measured in depressed patients receiving electroconvulsive therapy.

**Regulatory status:** Not approved anywhere. Developed academically in France (CNRS/Universite Cote d'Azur); no registered clinical trial of PE-22-28 has been published.

- In patch-clamp testing, PE-22-28 showed no inhibition of the related two-pore potassium channels TREK-2, TRAAK, TRESK, or TASK-1, indicating strong selectivity for TREK-1 within the K2P family tested. (evidence tier: in-vitro; [PMID 28955242](https://pubmed.ncbi.nlm.nih.gov/28955242/))
- In the original spadin work, the parent peptide produced antidepressant-like effects without changing locomotor activity and lost all activity in TREK-1 knockout mice, indicating on-target, non-stimulant action; these controls were run for spadin rather than PE-22-28 itself. (evidence tier: animal; [PMID 20405001](https://pubmed.ncbi.nlm.nih.gov/20405001/))
- The dose response is biphasic: 0.03 mcg/kg activated TREK-1 and was used for neuroprotection, while 3 mcg/kg blocked the channel for antidepressant-like effects, so dose direction determines which pharmacology an exposure produces. (evidence tier: animal; [PMID 31325429](https://pubmed.ncbi.nlm.nih.gov/31325429/))
- In treatment-resistant depressed patients, serum levels of the endogenous spadin-parent propeptide rose significantly one month after electroconvulsive therapy only in responders, linking the pathway to human treatment response without administering the peptide. (evidence tier: human-observational; [PMID 30233189](https://pubmed.ncbi.nlm.nih.gov/30233189/))

## Dosing Information (Research Context)

Published mouse studies used intraperitoneal doses of 3-4 mcg/kg in acute and 4-day sub-chronic antidepressant paradigms, or 1 mg/kg by oral gavage. A biphasic low dose of 0.03 mcg/kg intraperitoneally was used for TREK-1 activation and neuroprotection in a stroke model. No human dosing exists; microgram-scale schedules circulating online are extrapolations from these rodent protocols.

| Route | Dose | Frequency | Notes |
| --- | --- | --- | --- |
| Intraperitoneal (mouse) | 3-4 mcg/kg | Acute or once daily, 4-day paradigms | Antidepressant-like protocols, forced swim and novelty-suppressed feeding (PMID: 28955242) |
| Oral gavage (mouse) | 1 mg/kg | Once daily | Retained forced-swim activity, implying gut stability (PMID: 28955242) |
| Intraperitoneal, low-dose (mouse stroke model) | 0.03 mcg/kg | Once daily for 7 days post-ischemia | Biphasic TREK-1 activation for neuroprotection (PMID: 31325429) |

## Researched Effects

- **Rapid Antidepressant-Like Activity** (evidence: moderate): In the forced swim test, acute intraperitoneal PE-22-28 (3-4 mcg/kg) cut mouse immobility time by over 40% versus saline, and 4-day sub-chronic treatment reduced latency to eat in the novelty-suppressed feeding test; analogs remained active in learned-helplessness paradigms and after oral gavage (PMID: 28955242). Spadin-family peptides act within 4 days in these models, versus the weeks SSRIs require, because TREK-1 blockade raises serotonergic firing directly rather than through transporter adaptation (PMID: 20405001). All evidence is rodent behavioral pharmacology.
- **Selective TREK-1 Channel Blockade** (evidence: moderate): Patch-clamp on hTREK-1/HEK cells gave an IC50 of 0.12 nM for PE-22-28 versus 40 nM for spadin, with no inhibition of hTREK-2, hTRAAK, hTRESK, or hTASK-1, indicating strong selectivity within the two-pore potassium channel family (PMID: 28955242). Spadin-family blockade is allosteric and selective for arachidonic-acid-driven channel activation (PMID: 32317978). Target engagement by peptide is unusually well characterized for this class of research compound.
- **Hippocampal Neurogenesis** (evidence: moderate): Four days of treatment nearly doubled hippocampal BrdU-positive cell counts (about 1736 versus 899 per hippocampus in saline controls), with the G/A analog reaching about 2110, a readout the authors interpreted as induction of in vivo hippocampal neurogenesis matching the parent spadin profile (PMID: 28955242). Neurogenesis after days rather than weeks mirrors the rapid behavioral onset and distinguishes the mechanism from SSRI timelines.
- **Synaptogenesis (PSD-95 Upregulation)** (evidence: preliminary): On cultured mouse cortical neurons, PE-22-28 and its derivatives increased expression of PSD-95, a core postsynaptic density scaffold protein used as a synaptogenesis marker (PMID: 28955242). Related spadin work showed regulation of synaptogenesis in vitro and in vivo (PMID: 25598009). The finding links channel blockade to structural plasticity, though the molecular path from TREK-1 to PSD-95 is not fully mapped.
- **Stroke Recovery and Post-Stroke Depression** (evidence: preliminary): In a mouse focal-ischemia plus post-stroke-depression model, a very low dose of mini-spadin (0.03 mcg/kg, TREK-1 activating) given 30 minutes after ischemia onset protected against body-weight loss and delayed dopaminergic degeneration, while subsequent higher-dose (3 mcg/kg, TREK-1 blocking) treatment addressed depressive-like behavior (PMID: 31325429). This biphasic study is the first evidence of the peptide family in cerebrovascular injury, from the same academic group.

## Research Applications

- Depression Research
- Ion Channel Pharmacology
- Neurogenesis Studies
- Stroke Recovery Research
- Neuropsychopharmacology

## Key Studies

### Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design

Mazella J, Pétrault O, Lucas G, et al. — *PLoS Biology* (2010) — [PMID 20405001](https://pubmed.ncbi.nlm.nih.gov/20405001/)

The origin paper for the whole family: the authors showed that spadin, a 17-mer released from the sortilin propeptide, is an endogenous blocker of the TREK-1 potassium channel, that it increased serotonergic firing and produced antidepressant-like effects in forced swim, tail suspension, and conditioned suppression of motility tests, and that it induced hippocampal neurogenesis faster than fluoxetine. Spadin had no effect in TREK-1 knockout mice, proving on-target action, and did not alter locomotor activity. It established TREK-1 blockade as a rapid-acting antidepressant concept.

### Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity

Djillani A, Pietri M, Moreno S, et al. — *Frontiers in Pharmacology* (2017) — [PMID 28955242](https://pubmed.ncbi.nlm.nih.gov/28955242/) | [doi:10.3389/fphar.2017.00643](https://doi.org/10.3389/fphar.2017.00643)

The primary PE-22-28 paper. Starting from spadin's serum degradation products, the authors identified the 7-residue PE 22-28 as the shortest active fragment: IC50 0.12 nM on hTREK-1 (versus 40 nM for spadin), no activity at TREK-2, TRAAK, TRESK, or TASK-1, behavioral efficacy up to 23 hours (versus 7), activity after intraperitoneal (3-4 mcg/kg) and oral (1 mg/kg) dosing, near-doubling of hippocampal BrdU-positive cells after 4 days, and increased PSD-95 on cortical neurons. The G/A analog (AVSWGLR) showed the strongest neurogenesis. It is the citation behind essentially every vendor claim about PE-22-28.

### Retroinverso analogs of spadin display increased antidepressant effects

Veyssiere J, Moha Ou Maati H, Mazella J, et al. — *Psychopharmacology* (2015) — [PMID 25080852](https://pubmed.ncbi.nlm.nih.gov/25080852/)

This chemistry-driven study built retroinverso spadin analogs (reversed sequence with D-amino acids) seeking better affinity and action duration. The analogs retained TREK-1 blockade, showed increased antidepressant-like effects in behavioral tests, and induced neurogenesis, demonstrating that the spadin scaffold tolerates extensive stabilization engineering, the same logic later applied to PE-22-28 derivatives.

### First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides

Pietri M, Djillani A, Mazella J, et al. — *Neuropharmacology* (2019) — [PMID 31325429](https://pubmed.ncbi.nlm.nih.gov/31325429/)

In a mouse focal-ischemia and post-stroke-depression model, mini-spadin (PE 22-28) showed biphasic pharmacology: a single low dose (0.03 mcg/kg) after ischemia onset activated TREK-1 and protected against body-weight loss and delayed dopaminergic degeneration in the substantia nigra, while higher-dose treatment (3 mcg/kg) blocked TREK-1 for antidepressant-like effect. It is the first evidence of the peptide family in cerebrovascular injury and a crucial reminder that dose direction flips this compound's channel action.

### Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Ma R, Lewis A — *Frontiers in Pharmacology* (2020) — [PMID 32317978](https://pubmed.ncbi.nlm.nih.gov/32317978/) | [doi:10.3389/fphar.2020.00434](https://doi.org/10.3389/fphar.2020.00434)

An independent electrophysiology group dissected how spadin-family peptides interact with TREK-1, showing the block is selective for arachidonic-acid-mediated channel activation through an allosteric mechanism rather than pore occlusion. Activation-state selectivity offers a mechanistic explanation for the family's favorable preclinical side-effect profile compared with non-selective potassium channel blockers.

### Increased serum levels of sortilin-derived propeptide after electroconvulsive therapy in treatment-resistant depressed patients

Roulot M, Minelli A, Bortolomasi M, et al. — *Neuropsychiatric Disease and Treatment* (2018) — [PMID 30233189](https://pubmed.ncbi.nlm.nih.gov/30233189/)

The only human data adjacent to this peptide family: in 45 patients with treatment-resistant depression, serum levels of the endogenous sortilin propeptide (spadin's parent) did not differ from controls at baseline but rose significantly about one month after electroconvulsive therapy, and only in responders. Observational and measuring the endogenous peptide rather than administering it, the study nonetheless links the sortilin-propeptide pathway to human antidepressant response.

## Frequently Asked Questions

### What is PE-22-28 and how does it relate to spadin?

PE-22-28 is the shortest active fragment of spadin. Spadin is a 17-amino-acid peptide released from the propeptide of sortilin; by tracking spadin's degradation in mouse serum, researchers identified the 7-residue C-terminal piece (positions 22-28 of the propeptide, Gly-Val-Ser-Trp-Gly-Leu-Arg) as the minimal sequence that blocks TREK-1. PE-22-28 is about 300 times more potent than spadin (IC50 0.12 nM versus 40 nM) and lasts about three times longer in mice. It is also called mini-spadin.

### How does blocking TREK-1 produce antidepressant effects?

TREK-1 is a background potassium channel that keeps neurons electrically quiet. In the dorsal raphe, blocking it depolarizes serotonergic neurons and raises their firing rate, increasing serotonin output to mood circuits. SSRIs reach the same serotonergic endpoint indirectly through transporter inhibition and require weeks of adaptation; TREK-1 blockade acts directly, which is why spadin-family peptides produced antidepressant-like behavior in mice within 4 days. TREK-1 knockout mice are depression-resistant, validating the target genetically.

### Has PE-22-28 been studied in humans?

No. All PE-22-28 data is preclinical, from the French academic group that developed it and one independent electrophysiology study. The nearest human evidence is observational: serum levels of the endogenous parent propeptide rose after successful electroconvulsive therapy in treatment-resistant depression, linking the pathway to human antidepressant response without testing the peptide itself (PMID: 30233189).

### What is the biphasic dose effect?

PE-22-28 does not act the same way at every dose. At very low doses (0.03 mcg/kg in mice) it increased TREK-1 channel activity and was neuroprotective after experimental stroke; at higher doses (3 mcg/kg) it blocked the channel and produced antidepressant-like effects (PMID: 31325429). The two regimens have opposite channel actions, which makes uncontrolled dosing of this compound particularly poorly defined.

### How fast does PE-22-28 act compared to SSRIs?

In mouse models, antidepressant-like effects and hippocampal neurogenesis appear after 4 days of treatment, whereas SSRIs like fluoxetine require several weeks in the same paradigms (PMID: 28955242, 20405001). This is a rodent model comparison, not a human onset-of-action claim: no human has been dosed with PE-22-28 in a published study, and mouse depression tests do not map directly onto clinical response times.

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