PE-22-28: The Complete Guide

The widespread framing of PE-22-28 as a "BDNF fragment" is factually wrong. Existing StackTrax encyclopedia copy and most vendor descriptions repeat this error. The actual identity, anchored to the only published primary literature on the molecule:

• Sequence: Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR) — a heptapeptide.
• Origin: the C-terminal tail of spadin, a 17-amino-acid fragment of the propeptide region of sortilin (NTSR3) — encoded by the SORT1 gene.
• Mechanism: inhibition of the TREK-1 (KCNK2) two-pore-domain potassium channel. TREK-1 is a leak K⁺ channel; pharmacological inhibition produces antidepressant-like effects in rodent behavioral despair models.
• Mechanism is NOT BDNF / TrkB / neurotrophin signaling. PubMed searches for "PE 22-28 AND BDNF" and for the literal sequence GVSWGLR both return zero records.

The TREK-1 inhibition phenotype is mechanistically interesting (TREK-1 knockout mice show resistance to depression-like behavior in mouse models) but it’s a completely different mechanism from BDNF / TrkB signaling. Don’t conflate them.

PE-22-28 (also written PE 22-28) is a heptapeptide with sequence GVSWGLR. It is the C-terminal tail of spadin, which is itself a 17-amino-acid fragment of the propeptide region of sortilin (NTSR3 / SORT1).

The spadin family lineage:

• Sortilin (NTSR3 / SORT1) — an endogenous receptor protein. Its propeptide region is cleaved during processing.
• Spadin — a 17-aa fragment of the sortilin propeptide. Identified by the Borsotto / Lazdunski group at IPMC Sophia Antipolis (France) as a TREK-1 inhibitor with antidepressant-like activity. Founding paper: Mazella et al. 2010 (PMID 20405001, PLoS Biol).
• PE-22-28 — the C-terminal heptapeptide of spadin. Designed as a shorter, simpler analog. Founding paper: Djillani et al. 2017 (PMID 28955242, Front Pharmacol).
• Retro-inverso analogs — further development by the same group (Veyssière 2014, PMID 25080852).

The evidence base — one paper, one lab:

The entire PE-22-28-specific primary-literature record is a single 2017 paper (Djillani et al., PMID 28955242) from one French academic lab (Borsotto / Mazella / Heurteaux at IPMC Sophia Antipolis). All subsequent work cites it. The often-quoted "0.12 nM IC50" and "23-hour duration" figures both trace to this single source with no independent replication.

Regulatory status:

• FDA (US): never approved. No NDA, no IND on file. Sold as research chemical.
• EMA (EU): not approved.
• WADA 2026: not on the prohibited list by name. As an unapproved investigational substance, S0 (non-approved substances) catch-all may apply. Cleanest reading is S0 only — PE-22-28 doesn’t plausibly fall under S2 (no growth-factor-mimetic angle, no peptide-hormone classification).

TREK-1 (KCNK2) potassium channel:

• TREK-1 is a member of the K_2P (two-pore-domain) potassium channel family. It functions as a "leak" potassium channel — constitutively open, hyperpolarizing neurons.
• Highly expressed in serotonergic neurons of the dorsal raphe nucleus, where it modulates 5-HT firing.
• TREK-1 knockout mice show resistance to depression-like behavior in standard rodent paradigms (forced swim test, tail suspension, chronic mild stress) — the genetic anchor for the antidepressant hypothesis.
• Pharmacological TREK-1 inhibition by spadin / PE-22-28 produces a similar phenotype.

The proposed antidepressant mechanism:

1. PE-22-28 binds and inhibits TREK-1.
2. Reduced K⁺ leak in serotonergic neurons → depolarization → increased firing.
3. Enhanced serotonergic tone in mood-relevant circuits.
4. Effect timeline reported as faster than SSRIs in rodent behavioral despair tests.

Downstream effects characterized in the originating lab:

• Synaptogenesis — Devader 2015 (PMID 25598009) reports synaptogenic effects.
• CREB pathway activation — Daziano 2021 (PMID 33737242).
• Stroke / post-stroke depression — Daziano 2019 (PMID 31325429) extended into stroke models.

Independent TREK-1 axis confirmation:

Multiple non-Borsotto-group papers confirm TREK-1 as a relevant antidepressant target (PMIDs 32864894, 33348878, 33908633, 36670238, 26909044, 38807478). The TARGET is well-anchored. PE-22-28 as a tool compound is not.

Translational biomarker work in humans:

Sortilin propeptide levels in human serum / CSF have been studied as a biomarker in depression (Roulot 2018 PMID 30233189; Mazella 2025 PMID 40107034; Hermey 2018 PMID 27816451). This validates the sortilin-propeptide axis as relevant in human depression but does not establish PE-22-28 efficacy in humans.

Claim	Source	Status
TREK-1 inhibition by PE-22-28 (IC50 ~0.12 nM)	Djillani 2017 PMID 28955242	Single paper, single lab. No independent replication.
23-hour duration of action	Djillani 2017 PMID 28955242	Same single paper. Single rodent study.
Spadin parent antidepressant-like activity	Mazella 2010 PMID 20405001 + family review papers	Spadin (parent), not PE-22-28. Same Borsotto/Mazella group.
TREK-1 as antidepressant target	Multiple independent papers (PMIDs 32864884, 33348878, 33908633, 36670238, 26909044, 38807478)	Well-anchored target, but not specifically validating PE-22-28 as the right inhibitor.
Synaptogenesis / CREB / stroke effects	Devader 2015 (25598009); Daziano 2019 (31325429); Daziano 2021 (33737242)	All from the originating group; preclinical only.
Sortilin propeptide as human depression biomarker	Roulot 2018 (30233189); Mazella 2025 (40107034)	Translational biomarker work; validates the axis. Does NOT establish PE-22-28 efficacy in humans.
Human PK / efficacy / safety of PE-22-28	None	Zero human clinical trial data.
"BDNF fragment" / "neurotrophin signaling"	None — widespread misidentification in vendor copy	Factually wrong. PE-22-28 has nothing to do with BDNF.

Honest framing: PE-22-28 is a tool compound from one academic lab’s peptide-design effort, not a clinically validated drug. The TREK-1 antidepressant target is real; PE-22-28 as the way to drug it is one team’s proposal that has not been independently replicated.

• Half-life: Djillani 2017 reports a duration of action up to ~23 hours in mouse behavioral models. Plasma half-life specifically not characterized in published peer-reviewed PK studies. The 23-hour figure is single-source, single-lab.
• Routes used in published studies: intraperitoneal in mouse models. No human PK study.
• BBB penetration: inferred from CNS pharmacodynamic effects in rodents.
• Bioavailability: not measured in humans; rodent IP data only.

All vendor / community half-life and dose claims trace to one paper. Treat the numbers as preliminary, not validated.

StackTrax does not endorse PE-22-28 use. No published human trial. Community dosing extrapolates the Djillani 2017 mouse data to human weight.

Parameter	Common Range
Dose (intranasal)	200–500 µg/spray, 1–2 sprays/day
Dose (SC, less common)	100–500 µg/day
Frequency	Daily; some users every-other-day given the claimed long duration
Cycle length	2–6 weeks (community)
Route	Intranasal most common; SC less common

None of these dose figures is anchored to any published human trial.

For a typical 2 mg lyophilized vial:

• Add 2 mL bacteriostatic water → 1 mg/mL (1000 µg/mL).
• On a U-100 insulin syringe, 1 unit = 10 µg.
• For a 200 µg intranasal dose — 0.2 mL (20 units).

Storage:

• Lyophilized: stable at room temperature short-term; refrigerate for longer.
• Reconstituted: refrigerate. Use within 28 days.

For the full reconstitution protocol, see the Bacteriostatic Water guide.

No published human safety data on PE-22-28. No FAERS, EudraVigilance, or Yellow Card entries.

From rodent data + extrapolation:

• Generally well-tolerated in the mouse models reported by the originating lab.
• Spadin-family safety (rodent battery, Moha Ou Maati 2012, PMID 22022421) was reported as benign over the doses tested.

Theoretical concerns:

• SSRI stacking concern. SSRIs already amplify serotonergic tone; TREK-1 inhibition adds another layer. Stacking PE-22-28 with an SSRI is a double-mechanism serotonergic intervention with no safety data. This is the most important practical caveat.
• Cardiac: TREK-1 has roles in cardiac repolarization. Chronic systemic inhibition is uncharacterized for arrhythmia risk.
• Anesthetic interactions: TREK-1 is implicated in volatile-anesthetic action. PE-22-28 effect during surgical anesthesia uncharacterized.
• Long-term safety: zero data beyond ~weeks of dosing in any species.

• Pregnancy / breastfeeding — no safety data; default contraindication.
• Concurrent SSRIs / SNRIs / MAOIs — double-mechanism serotonergic intervention; no safety data; physician supervision required if combined.
• Active suicidal ideation or severe MDD — not a substitute for evidence-based treatment.
• Cardiac arrhythmia history — theoretical TREK-1 inhibition concern for repolarization.
• Upcoming surgery / anesthesia — uncharacterized interaction with volatile anesthetics; discontinue ahead of any procedure.
• Athletes subject to anti-doping testing — consult your governing body. WADA S0 catch-all may apply.

Compound	Difference from PE-22-28
BDNF (Brain-Derived Neurotrophic Factor)	PE-22-28 is NOT a BDNF fragment. BDNF is a 119-aa neurotrophin protein that signals via TrkB. PE-22-28 (GVSWGLR) is unrelated by sequence and unrelated by mechanism. The "BDNF fragment" framing in vendor copy is factually wrong.
Spadin (parent)	17-aa parent peptide; PE-22-28 is its C-terminal heptapeptide. Same TREK-1 mechanism.
7,8-Dihydroxyflavone	Small-molecule TrkB agonist. Different target (TrkB vs TREK-1). Sometimes lumped with PE-22-28 in vendor catalogs but mechanistically unrelated.
SSRIs (fluoxetine, sertraline, escitalopram)	Serotonin reuptake inhibitors. PE-22-28 doesn’t inhibit SERT; amplifies serotonergic firing via TREK-1 inhibition. Different mechanism, theoretically additive. Stacking is uncharacterized.
Ketamine / esketamine (Spravato)	NMDA antagonist; rapid-acting via glutamatergic / synaptogenesis pathway. Different mechanism. Both are "fast-acting antidepressant" candidates but mechanistically distinct.
Dihexa	HGF/c-Met positive modulator (peptide-derived). Different mechanism. Dihexa’s foundational papers were retracted; PE-22-28’s aren’t but rest on a single 2017 paper.
NSI-189 / amdiglurax	Small-molecule investigational antidepressant; phenotypic-screen origin; failed two Phase 2 MDD trials. Different mechanism (uncharacterized) and different evidence trajectory.
Semax / Selank	Russian-origin nootropic peptides. Different mechanisms (BDNF / NGF for Semax; GABAergic for Selank). PE-22-28 is from a French academic lab (Borsotto/Mazella) with a different research lineage.
MIF-1	D2 PAM mechanism. Different target.