PE-22-28

What is PE-22-28?

PE 22-28 is a seven-amino-acid peptide corresponding to residues 22 to 28 of the sortilin propeptide, and it is a fragment of spadin rather than a separate discovery. Spadin is PE 12-28, a 17-residue peptide identified in 2010 as an endogenous TREK-1 blocker with antidepressant activity. Studying spadin's breakdown products in blood led the same group to the shorter sequence, published in 2017 as PE 22-28 and referred to elsewhere in their work as mini-spadin. The shortening was a substantial improvement on paper. PE 22-28 binds TREK-1 with an IC50 of 0.12 nM against spadin's 40 to 60 nM — roughly 400-fold tighter — and its duration of action extends to about 23 hours against spadin's 7. In rodent behavioural models it reduced immobility in forced swimming, shortened latency in novelty-suppressed feeding after four days of dosing, induced hippocampal neurogenesis after only four days, and increased PSD-95 as a marker of synaptogenesis in cortical neurons. Two things complicate the simple description of it as a TREK-1 blocker, and both belong near the top. First, its action is biphasic: in the stroke study from the originating group, a single low dose of 0.03 µg/kg was used specifically 'to activate TREK-1' for neuroprotection while 3 µg/kg was used 'to inhibit TREK-1' for antidepressant effect, with the authors stating plainly that 'at low doses, the channel activity was increased whereas at higher doses it was inhibited'. Second, the only independent electrophysiological examination of the parent compound found that spadin did not block basal TREK-1 current at all, instead selectively antagonising arachidonic-acid activation of the channel by an apparently allosteric mechanism. There are three papers on this molecule in the entire literature, and the laboratory that produced them has published no spadin or TREK-1 work since 2019.

What PE-22-28 Is Investigated For

The interesting thing about PE 22-28 is that the target looks better supported than the compound. TREK-1 as an antidepressant target has accumulated genuinely independent support. Sortilin-knockout mice show reduced depressive-like behaviour; independent Chinese groups have compared TREK-1 blockers against fluoxetine and reported earlier and more pronounced effects; an independent Korean group showed that mosapride produces rapid antidepressant action by internalising a TREK1-HTR4 complex; and in 2026 an independent Chinese group reported that TREK-1 is a key target of (2R,6R)-hydroxynorketamine, ketamine's active metabolite, inhibited at an IC50 close to its antidepressant concentration. That last result is the most consequential thing to happen to this mechanism, because it connects TREK-1 to the one fast-acting antidepressant class with real human validation. PE 22-28 itself has three papers. The 2017 characterisation, a 2019 stroke study, and a 2021 paper on beta-cell survival. No human has received it, no human has received spadin, and no TREK-1 blocker of any kind has entered a clinical trial for depression. The onset claim needs attributing carefully. 'Works in days rather than weeks' traces to spadin, where the original report described effects within 4 days that classical antidepressants needed 21 days to achieve. Independent head-to-head comparisons against fluoxetine used spadin or other TREK-1 blockers, not PE 22-28, and PE 22-28's own paper contains no SSRI arm. The speed claim belongs to the class, not to this peptide specifically. Human biomarker work showing sortilin-derived propeptide levels are altered in major depression and shift after electroconvulsive therapy supports the pathway's relevance. It is not evidence for the compound, and an earlier version of this page tagged three such observational studies as clinical trials, which sat awkwardly against its own correct statement that PE 22-28 has never been tested in humans.

History & Discovery

PE-22-28 emerged from a research program led by Marc Borsotto, Catherine Heurteaux, and Michel Lazdunski at the Institut de Pharmacologie Moléculaire et Cellulaire (IPMC) in Valbonne, France. The program's starting point was TREK-1, a two-pore-domain potassium channel that — based on knockout mouse work from the same lab — appeared to play a central role in vulnerability to depression: TREK-1-deficient mice were strikingly resistant to depressive behavior in standard rodent assays. The Borsotto group identified spadin, a peptide cleaved from the propeptide region of sortilin (a receptor protein with roles in neurotrophin signaling and lipid handling), as an endogenous TREK-1 blocker. In rodent models, spadin produced antidepressant-like effects within days, in contrast to the several-week onset typical of SSRIs and SNRIs. PE-22-28 is a shortened, optimized analog of spadin — designed with improved metabolic stability, retained TREK-1 inhibition, and a similar fast-onset antidepressant profile in animal models. The translational arc has been notable on two fronts. First, biomarker work in human depression has confirmed that sortilin-derived propeptide levels are altered in patients with major depressive disorder and shift after electroconvulsive therapy, which validates the underlying TREK-1/sortilin pathway as relevant to human depression. Second, despite this, PE-22-28 itself has not advanced to human clinical trials. The compound exists in the published literature as a preclinical antidepressant tool and in the research-chemical market as a 'mood' peptide with no human evidence base. Independent 2026 work has begun to broaden the TREK-1/rapid-antidepressant story beyond the French-lab lineage: a Molecular Psychiatry paper (PMID 42542439) from a separate group identified a TREK1-HTR4 receptor complex and showed the HTR4 agonist mosapride internalizes TREK-1 and produces fast-onset antidepressant-like effects — a mechanistically parallel replication of the 'TREK-1 downregulation → rapid antidepressant' concept using a different molecular starting point.

How It Works

TREK-1 is a potassium channel that acts like a brake on how readily certain brain cells fire, and mice lacking it are unusually resistant to depression. PE-22-28 interferes with that brake, which in rodents lifts mood within days and encourages new connections between neurons. The complication is that the effect reverses at low doses, where the peptide activates the channel instead of inhibiting it.

TREK-1 is a two-pore-domain potassium channel expressed in mood-regulating regions, and the case for targeting it begins with genetics: TREK-1 knockout mice are resistant to depressive-like behaviour, and sortilin-deficient mice show the same phenotype through altered TREK-1 function. Reducing TREK-1 activity increases neuronal excitability in serotonergic circuits and is associated with BDNF expression, hippocampal neurogenesis and synaptogenesis. PE 22-28 engages this target with an IC50 of 0.12 nM, against 40 to 60 nM for spadin, and holds its effect for roughly 23 hours rather than 7. On the strength of those numbers it is routinely described as a potent, selective TREK-1 blocker. Two findings complicate that description and neither is widely repeated. The first is biphasic action. In the originating group's own stroke study, a low dose of 0.03 µg/kg was administered specifically 'to activate TREK-1' and produce neuroprotection, while 3 µg/kg was used 'to inhibit TREK-1' for antidepressant effect — the authors describing a biphasic action in which channel activity increased at low doses and was inhibited at higher ones. A dose below the therapeutic window does not simply produce a smaller antidepressant effect; it engages the channel in the opposite direction. The second is that the only independent electrophysiological test of the parent compound did not reproduce basal blockade. Working in Xenopus oocytes, an independent UK group found that 'under basal conditions, both TREK-1 and TREK-2 currents were insensitive to application of spadin', and that spadin also failed to inhibit currents activated chemically or by a gating mutation. What it did do was perturb subsequent activation by arachidonic acid, leading to the conclusion that spadin 'specifically antagonizes the activation of TREK-1 channels by AA, likely via an allosteric mechanism'. That is a conditional, state-dependent antagonism rather than channel blockade, and if it carries over to PE 22-28 it changes what the compound is. TREK-1 is also not confined to the brain. It is expressed in cardiac and smooth muscle, and in pancreatic beta cells spadin potentiated calcium influx and insulin secretion, raising plasma insulin after glucose in mice. A systemic TREK-1 modulator has a cardiovascular and endocrine profile whether or not anyone has looked for one.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about PE-22-28:

• 01Any human clinical trial — no published Phase I, II, or III study has tested PE-22-28 in humans for safety, pharmacokinetics, dose-response, or efficacy.
• 02Cardiovascular safety of TREK-1 blockade in humans — TREK-1 is expressed in cardiac and vascular tissues, and the long-term cardiovascular consequences of pharmacologic channel blockade are uncharacterized.
• 03Comparative efficacy vs. ketamine, esketamine, and other fast-acting antidepressants — the only validated rapid-onset antidepressants in humans work through different mechanisms; PE-22-28 has never been compared.
• 04Independent preclinical replication outside the originating Borsotto/IPMC program — replication in independent labs is sparse but has grown. A 2026 Molecular Psychiatry paper from an independent group (PMID 42542439) identifies a TREK1-HTR4 receptor complex and shows the HTR4 agonist mosapride internalizes TREK1 and produces fast-onset antidepressant-like effects — a mechanistically parallel (though not spadin-based) replication of the 'TREK-1 downregulation → fast antidepressant' concept from outside the French lab lineage that dominates the spadin literature. A 2026 Channels review (PMID 42153246) frames TREK-1 as a polymodal cell-activity regulator and flags the ongoing limitation of subtype-selective pharmacology.
• 05Pharmacokinetics in humans — absorption, distribution, metabolism, and excretion have not been characterized in any species relevant to predicted human exposure at proposed doses.
• 06Long-term effects on BDNF, neurogenesis, and synaptic plasticity in chronic dosing — preclinical work has used short courses, and chronic neuroplastic consequences are unknown.

Forms & Administration

Intraperitoneal injection in essentially all published work, at 3.0 to 4.0 µg/kg — roughly thirty times lower than spadin's 100 µg/kg, a distinction secondary sources routinely collapse. Notably, the originating paper also reported that the analogues 'were also efficient after gavage, indicating that these molecules could be administered per os', with oral dosing at 1 mg/kg remaining active in the forced swimming test; an earlier version of this page stated the opposite. No subcutaneous or intranasal study of PE 22-28 exists in the literature, and no pharmacokinetic study in any species has been published. There is no human formulation and no approved product.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

PE-22-28 has never been tested in humans in a published clinical trial and is not approved for any indication anywhere. The fast-onset antidepressant profile in animal models is preclinical and does not constitute evidence of safety or efficacy in human depression. Self-administration as a 'mood' peptide carries entirely uncharacterized risk.

Timeline of Effects

Common Questions

Who PE-22-28 Is NOT For

Drug & Supplement Interactions

There are no published clinical drug-interaction studies for PE-22-28 in humans. What follows is mechanistic inference, not documented interaction data. The most plausible theoretical concerns involve other antidepressants and CNS-active medications. SSRIs, SNRIs, MAOIs, atypical antidepressants, and ketamine all act through pathways that intersect with TREK-1 biology in some way (TREK-1 modulates serotonergic neuron excitability, among other effects). Combined use is unstudied; theoretical risks include serotonin syndrome (with serotonergic agents), excessive mood effects, and unpredictable response. With antiarrhythmic drugs and any agent with QT-prolonging or potassium-channel-modulating activity, TREK-1 blockade introduces an additional cardiac electrophysiologic variable that has not been characterized in humans. With benzodiazepines and other GABAergic sedatives, additive CNS depression is plausible but unstudied. No specific concerns have been documented with cardiovascular, metabolic, or endocrine medications, but the absence of documentation reflects the absence of human use, not the absence of risk. Patients on any regular medication should not co-administer PE-22-28 without disclosure to their prescriber — and the responsible answer in most cases is not to use PE-22-28 at all.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions