PE-22-28: Emerging Nootropic Peptide Research

Among the newer entries in the nootropic peptide space, PE-22-28 occupies a genuinely interesting position. It emerged from a lab at the Universite Cote d'Azur in France, where researchers studying the neurobiology of depression found that a tiny fragment of the protein sortilin had potent effects on mood, neuronal growth, and brain recovery after injury.

That fragment -- a seven-amino-acid peptide with the sequence Gly-Val-Ser-Trp-Gly-Leu-Arg -- is PE-22-28. Published research remains limited to a handful of preclinical studies from one research group. No human trials have been conducted. But the early data has generated considerable interest among neuroscience researchers and the nootropics community alike.

What makes PE-22-28 worth watching is its target: a potassium channel called TREK-1 that has emerged as one of the more compelling molecular links between ion channel activity and depressive behavior. The peptide blocks this channel with extraordinary potency -- hundreds of times more effectively than its parent compound -- and in rodent models, that blockade translates into antidepressant-like behavior, new hippocampal neuron growth, and protection against stroke damage.

Table of Contents

Quick Facts
What Is PE-22-28?
The Sortilin Connection
How PE-22-28 Works: Mechanisms of Action
Research Evidence
Administration and Dosing
Safety Profile and Side Effects
Legal and Regulatory Status
Limitations of Current Research
Frequently Asked Questions
The Bottom Line

Quick Facts

Property	Detail
Full Name	PE-22-28 (also called Mini-Spadin)
Type	Synthetic peptide (shortened spadin analog)
Amino Acid Sequence	GVSWGLR (7 amino acids)
Molecular Weight	773.89 Da
Molecular Formula	C35H55N11O9
CAS Number	1801959-12-5
Primary Target	TREK-1 potassium channel (KCNK2)
IC50 for TREK-1	0.12 nM
Derived From	Sortilin propeptide (PE)
Parent Compound	Spadin (PE 12-28, 17 amino acids)
Research Stage	Preclinical (animal studies only)
Key Researchers	Jean Mazella, Marc Borsotto, Catherine Heurteaux (Universite Cote d'Azur, France)

What Is PE-22-28?

PE-22-28 is a synthetic peptide consisting of seven amino acids, corresponding to positions 22 through 28 of a naturally occurring propeptide called PE. It was developed as a shortened, more stable version of spadin, a 17-amino-acid peptide that French researchers first described in 2010 as a novel antidepressant.

The name follows a simple convention: "PE" refers to the parent propeptide, and "22-28" indicates the amino acid positions it spans. In the literature, you may also see it called "Mini-Spadin" -- the minimal active fragment of the original spadin sequence.

What distinguishes PE-22-28 from other nootropic peptides is its mechanism. While Semax and Selank work through neurotransmitter systems and neurotrophic factors, PE-22-28 targets an ion channel -- a two-pore-domain potassium channel called TREK-1. Blocking this channel affects neuronal excitability in ways linked to mood regulation, neuroplasticity, and neuroprotection.

The compound was first described in a 2017 paper in Frontiers in Pharmacology by Djillani, Pietri, and colleagues at the Institut de Pharmacologie Moleculaire et Cellulaire in Valbonne, France. Follow-up studies from the same group have explored applications in stroke recovery, post-stroke depression, and pancreatic beta-cell survival.

The Sortilin Connection

The story begins with sortilin (also known as neurotensin receptor-3, or NTSR3), a sorting receptor on the surface of neurons and other cells. Sortilin is produced as a larger precursor, pro-sortilin, which must be cleaved by the enzyme furin to become functional. That cleavage releases a 44-amino-acid fragment called the propeptide, or PE.

In 2010, Jean Mazella and colleagues at the French National Centre for Scientific Research (CNRS) discovered that this fragment was not molecular waste. PE -- and a synthetic version called spadin (amino acids 12-28 of PE) -- could block TREK-1 potassium channels and produce antidepressant-like effects in mice. The work, published in PLoS Biology, has been cited over 200 times.

Spadin had a problem: it degraded quickly in the bloodstream. Its effects lasted roughly seven hours in rodents. So the team searched for the smallest effective fragment that retained TREK-1 blocking activity with better stability.

That search led to PE-22-28. By studying spadin's blood degradation products and testing shortened fragments, Djillani et al. (2017) identified this seven-amino-acid stretch as the sweet spot. PE-22-28 blocked TREK-1 with an IC50 of 0.12 nM -- roughly 350 to 500 times more potent than spadin -- and its duration of action stretched to approximately 23 hours, more than three times longer.

How PE-22-28 Works: Mechanisms of Action

TREK-1 Channel Blockade

The primary mechanism of PE-22-28 is inhibition of TREK-1, a member of the two-pore-domain potassium channel family (K2P channels). TREK-1, encoded by the gene KCNK2, is one of the most widely expressed background potassium channels in the mammalian brain.

TREK-1 channels act as "leak" channels -- they allow potassium ions to flow out of neurons at rest, maintaining the resting membrane potential and making neurons less excitable. They are opened by membrane stretch, arachidonic acid, heat, and certain anesthetics.

The connection between TREK-1 and depression was established in 2006, when Heurteaux et al. found that mice lacking the TREK-1 gene displayed a striking behavioral profile: reduced immobility in the forced swim test and tail suspension test (standard measures of depression-like behavior), increased serotonergic neurotransmission in the dorsal raphe nucleus, and resistance to depression-like states. Deleting TREK-1 made mice behave as though they were on antidepressants.

PE-22-28 blocks TREK-1 with an IC50 of 0.12 nM. The peptide selectively antagonizes TREK-1 activation by arachidonic acid rather than acting as a direct pore blocker. This selectivity may explain why it produces antidepressant effects without disrupting other TREK-1 functions like pain sensing and ischemic neuroprotection.

Downstream Signaling Effects

Blocking TREK-1 increases neuronal excitability, which triggers a cascade of downstream effects:

Increased serotonergic activity. TREK-1 is expressed in serotonin-producing neurons of the dorsal raphe nucleus. Blocking the channel increases the firing rate of these neurons, raising serotonin levels in target brain regions -- a mechanism shared with conventional SSRI antidepressants, but achieved through an entirely different molecular pathway.
Hippocampal neurogenesis. One of the most consistent findings across spadin and PE-22-28 studies is an increase in new neuron formation in the hippocampus. In the 2017 study, PE-22-28 induced significant neurogenesis after only four days of treatment, as measured by BrdU labeling of dividing cells in the dentate gyrus. This rapid timeline is notable because most conventional antidepressants require weeks to produce measurable neurogenic effects.
Synaptogenesis. Research on spadin showed that TREK-1 blockade promotes new synapse formation. Devader et al. (2015, British Journal of Pharmacology) demonstrated that spadin increased dendritic spine density and upregulated synapse-related proteins including PSD-95 and synapsin. PE-22-28, as a more potent TREK-1 inhibitor, is expected to produce similar or stronger effects.
CREB signaling pathway activation. Daziano et al. (2021, Pharmacological Research) found that PE-22-28 activates the CaMK/CREB signaling pathway. CREB (cAMP response element-binding protein) has well-established roles in memory formation, neuronal survival, and neuroplasticity -- making this finding relevant to the peptide's potential cognitive effects.

Research Evidence

Antidepressant Activity (Djillani et al., 2017)

The foundational study was published in Frontiers in Pharmacology by Djillani, Pietri, Moreno, Heurteaux, Mazella, and Borsotto. They tested PE-22-28 alongside several analogs using established rodent depression models.

In the forced swim test, mice treated with PE-22-28 showed significantly reduced immobility time -- a standard indicator of antidepressant-like activity. The peptide performed comparably to or better than spadin, despite being less than half its size.

In the novelty suppressed feeding test, four days of PE-22-28 treatment significantly reduced the latency for mice to eat in a novel, anxiety-provoking environment. This test is notable because it responds to chronic but not acute antidepressant treatment -- yet PE-22-28 showed effects in just four days.

The study also documented rapid hippocampal neurogenesis and confirmed the improved TREK-1 binding affinity and in vivo stability.

Stroke Recovery and Post-Stroke Depression (Pietri et al., 2019)

Published in Neuropharmacology, this study extended the research into stroke. Pietri et al. tested spadin and PE-22-28 in rodent ischemic stroke models and found protection on multiple fronts: reduced motor deficits, improved cognitive outcomes, and decreased apoptotic cell death in affected brain regions.

Post-stroke depression -- the most common mood disorder following stroke, affecting roughly 30% of survivors -- also responded to treatment. This dual activity against stroke damage and subsequent depression has made the TREK-1 pathway a topic of growing interest.

A 2025 human observational study by Mazella et al. (Journal of the Neurological Sciences) found that serum sortilin-derived propeptide levels were decreased in patients with post-stroke depression. Earlier work by Devader et al. (2017) had shown that PE concentrations were decreased in patients with major depressive disorder, and the 2025 stroke study extends this biomarker finding into post-stroke populations.

Pancreatic Beta-Cell Protection (Daziano et al., 2021)

Daziano et al. showed that PE-22-28 (called Mini-Spadin in this study) protects pancreatic beta cells from apoptosis caused by inflammatory and metabolic stress, working through the CaMK/CREB signaling pathway. While not directly related to nootropic applications, this finding suggests that PE-22-28's neuroprotective effects may operate through similar cell-survival mechanisms.

Comparison with Other Nootropic Peptides

PE-22-28 occupies a distinct mechanistic niche among cognitive peptides:

Peptide	Primary Mechanism	Research Stage
PE-22-28	TREK-1 potassium channel blockade	Preclinical only
Semax	Melanocortin system / BDNF	Clinical use in Russia
Selank	GABA modulation / enkephalin metabolism	Clinical use in Russia
Dihexa	HGF/c-Met receptor activation	Preclinical only
Cerebrolysin	Neurotrophic factor mixture	Approved in 30+ countries

PE-22-28 remains firmly in the lab, while the others have varying degrees of clinical experience. Its advantage is theoretical precision -- it hits a specific, well-characterized molecular target -- but this has not yet been validated in human subjects.

Administration and Dosing

PE-22-28 has not been evaluated in human clinical trials, and no established dosing protocols exist for humans. All dosing information available pertains to preclinical research contexts.

In the published animal studies:

Route: Intraperitoneal (IP) injection was the primary route used in rodent studies.
Doses tested: Typically in the range of 100 micrograms per kilogram of body weight in mice.
Duration of effect: Approximately 23 hours per dose, based on in vivo TREK-1 inhibition duration data from Djillani et al. (2017).
Treatment duration: Behavioral and neurogenic effects were observed with sub-chronic treatment periods of four days in most study protocols.

The compound is soluble in water to at least 2 mg/mL, according to Tocris/Bio-Techne product data. It should be stored at -20 degrees Celsius.

Some practitioners have explored intranasal administration, based on the general principle that small peptides can cross nasal mucosa to reach the brain. No published research has tested PE-22-28 via this route, and bioavailability data for intranasal delivery does not exist.

Important: Any discussion of dosing here is provided strictly for educational context. PE-22-28 is a research compound, not an approved therapeutic.

Safety Profile and Side Effects

The safety data on PE-22-28 is extremely limited -- a direct consequence of the compound's early research stage and the small number of published studies.

What can be said:

No toxic effects reported in rodent studies. The published papers did not report significant adverse effects at the doses tested. Formal toxicology studies (chronic dosing, organ pathology, reproductive toxicity) have not been published.
TREK-1 blockade appears functionally selective. A 2012 study on spadin (Maati et al., Neuropharmacology) tested whether TREK-1 blockade interfered with pain perception, epilepsy susceptibility, or ischemic neuroprotection. Spadin did not worsen any of these conditions, suggesting functional selectivity. PE-22-28 may share this profile.
Theoretical concerns exist. TREK-1 channels play roles in cardiac function, body temperature regulation, and anesthetic sensitivity. Long-term blockade could, in principle, produce side effects in these domains. No data exists to confirm or rule this out.
No human safety data. Zero human subjects have been exposed to PE-22-28 in any published study.

Legal and Regulatory Status

PE-22-28 is not approved for human use by the FDA, EMA, or any other national regulatory authority. It exists in the same regulatory gray zone as many research peptides:

Research use only. The compound is commercially available from specialty chemical suppliers like Tocris/Bio-Techne as a research reagent. These products are labeled explicitly as not intended for human consumption.
Not a scheduled substance. PE-22-28 is not a controlled substance in the United States, EU, or most other jurisdictions. The absence of scheduling does not mean its sale for human consumption is legal.
FDA regulatory environment. The broader regulatory environment for peptides has tightened since 2023, when the FDA began restricting compounding pharmacies from producing certain peptide products. PE-22-28 is not among the peptides specifically targeted (those actions focused primarily on GLP-1 agonists and compounds like BPC-157), but the regulatory trend points toward greater scrutiny of unapproved peptide products.
WADA status. PE-22-28 does not appear on the World Anti-Doping Agency's prohibited list as of 2026. Athletes should note that WADA's list is updated annually and pharmacologically active substances can be prohibited even if not named specifically.

Limitations of Current Research

PE-22-28 is among the least clinically validated peptides in the nootropic space. Honest assessment of the evidence requires acknowledging several significant limitations:

All published research comes from one laboratory. Every study on PE-22-28 was conducted by the same group at the Universite Cote d'Azur / CNRS in Valbonne, France. Independent replication -- the gold standard for scientific confidence -- has not occurred.

No human data exists. PE-22-28 has not entered clinical trials. There are no Phase 1 safety studies, no pharmacokinetic data in humans, no dose-finding studies, and no efficacy data in human subjects.

Animal models have well-known limitations. The forced swim test and novelty suppressed feeding test are screening tools, not direct measures of human depression or cognition. Many compounds that show promise in these models fail to translate into effective human treatments.

Neurogenesis claims require context. PE-22-28 stimulates new neuron growth in rodent hippocampus, but the functional significance of adult hippocampal neurogenesis in humans remains actively debated.

Long-term safety is unknown. The longest treatment period in published studies is measured in days, not months or years. The consequences of sustained TREK-1 blockade are not known.

Commercial availability does not equal clinical validation. Availability from research chemical suppliers does not mean PE-22-28 has been shown safe or effective for any human condition.

Frequently Asked Questions

Is PE-22-28 the same as spadin?

No. PE-22-28 is a shortened analog of spadin. Spadin (PE 12-28) is a 17-amino-acid peptide derived from positions 12 through 28 of the sortilin propeptide. PE-22-28 corresponds to only the last seven amino acids of that sequence (positions 22-28). Despite being much smaller, PE-22-28 is roughly 350 to 500 times more potent at blocking the TREK-1 channel and lasts approximately three times longer in vivo.

No. Some online sources incorrectly describe PE-22-28 as a fragment of PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide). PE-22-28 is derived from the propeptide of sortilin and has no structural or functional relationship to PACAP or the PAC1 receptor.

How does PE-22-28 compare to other nootropic peptides?

PE-22-28 blocks an ion channel, while Semax and Selank modulate neurotransmitter systems, and Dihexa activates growth factor receptors. The most important practical difference: Semax, Selank, and Cerebrolysin have clinical data in humans. PE-22-28 does not.

Can PE-22-28 cross the blood-brain barrier?

The published research used intraperitoneal injection in rodents and observed central nervous system effects (behavioral changes, hippocampal neurogenesis), which implies the compound or its active metabolites reach the brain. Its small size (7 amino acids, ~774 Da) is consistent with molecules that can cross the barrier, but direct blood-brain barrier permeability studies have not been published.

Has PE-22-28 been tested in humans?

No. As of early 2026, no human clinical trials of PE-22-28 have been registered or published. All data comes from in vitro cell studies and in vivo rodent experiments.

What is the TREK-1 channel and why does it matter for mood?

TREK-1 (TWIK-Related K+ channel 1, gene: KCNK2) is a background potassium channel expressed throughout the brain. It regulates neuronal excitability by allowing potassium ions to leak out of neurons, keeping them in a less excitable state. Mice lacking TREK-1 behave as though they are on antidepressants -- showing increased serotonin neurotransmission, resistance to stress-induced depression, and improved behavioral test performance. This makes TREK-1 a target of interest for antidepressant drug development.

Is PE-22-28 legal to purchase?

PE-22-28 is available from research chemical suppliers for laboratory use. It is not a controlled or scheduled substance. However, it is not approved for human consumption, and purchasing it for self-administration falls outside the intended use sanctioned by manufacturers and regulators.

The Bottom Line

PE-22-28 is a seven-amino-acid peptide that blocks the TREK-1 potassium channel with remarkable potency. In rodent studies, this translates into rapid antidepressant-like effects, hippocampal neurogenesis, and protection against stroke-induced brain damage. The compound is more potent and longer-lasting than its parent molecule spadin, and it works through a mechanism distinct from conventional antidepressants and other nootropic peptides.

But context matters enormously here. The total published literature on PE-22-28 consists of a small number of papers, all from the same French research group, all in animal models. No human has been given this compound in a clinical trial. No independent laboratory has replicated the findings.

For those interested in the best peptides for cognitive enhancement, PE-22-28 is best understood as a compound to watch, not one to act on. The TREK-1 pathway has legitimate credentials as a target for mood and cognitive disorders. But the gap between "promising rodent data" and "works safely in humans" is wide, and it has swallowed countless compounds that looked good in mice.

If you are considering any peptide for cognitive or mood-related purposes, the conversation starts with a qualified healthcare provider. Compounds with actual clinical data, like Cerebrolysin or Semax, offer a stronger evidence base. PE-22-28 represents a compelling hypothesis backed by early-stage evidence. Whether it becomes something more depends on the rigorous, independent clinical research that has not yet begun.