A 7-amino-acid peptide (GVSWGLR) derived from the C-terminal tail of spadin, a fragment of the sortilin (NTSR3) propeptide. Mechanism: TREK-1 (KCNK2) two-pore-domain potassium channel inhibition — not BDNF signaling, despite widespread vendor framing.
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: PE-22-28 is the heptapeptide Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR), the C-terminal tail of spadin — a 17-amino-acid fragment of the propeptide region of sortilin (NTSR3, encoded by SORT1). Mechanism is inhibition of the TREK-1 (KCNK2) two-pore-domain potassium channel; TREK-1 is a leak K+ channel, and 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) 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's 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) is an endogenous receptor protein whose propeptide region is cleaved during processing; spadin is a 17-aa fragment of that 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 is the C-terminal heptapeptide of spadin, designed as a shorter, simpler analog (Djillani et al. 2017, PMID 28955242, Front Pharmacol); retro-inverso analogs were developed later by the same group (Veyssière 2014, PMID 25080852).
The entire PE-22-28-specific primary-literature record is a single 2017 paper from one French academic lab (Borsotto / Mazella / Heurteaux). 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.
TREK-1 (KCNK2) is a member of the K2P two-pore-domain potassium channel family — a "leak" K+ channel that's constitutively open and hyperpolarizing. It's 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, 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: PE-22-28 binds and inhibits TREK-1, reducing K+ leak in serotonergic neurons → depolarization → increased firing → enhanced serotonergic tone in mood-relevant circuits. Effect timeline reported as faster than SSRIs in rodent behavioral despair tests.
Downstream effects characterized in the originating lab: synaptogenesis (Devader 2015, PMID 25598009), CREB pathway activation (Daziano 2021, PMID 33737242), and effects in stroke / post-stroke depression models (Daziano 2019, PMID 31325429).
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 isn't.
Translational biomarker work in humans: sortilin propeptide levels in human serum / CSF have been studied as a depression biomarker (Roulot 2018 PMID 30233189; Mazella 2025 PMID 40107034; Hermey 2018 PMID 27816451). This validates the sortilin-propeptide axis as relevant in human depression but doesn't establish PE-22-28 efficacy in humans.
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Start Tracking Free| 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 group. |
| TREK-1 as antidepressant target | Multiple independent papers | Well-anchored target, not specifically validating PE-22-28 as the right inhibitor. |
| Synaptogenesis / CREB / stroke effects | Devader 2015; Daziano 2019, 2021 | All from the originating group; preclinical only. |
| Sortilin propeptide as human biomarker | Roulot 2018; Mazella 2025 | Validates the axis. Doesn't 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 | Factually wrong. PE-22-28 has nothing to do with BDNF. |
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 hasn't been independently replicated.
Djillani 2017 reports a duration of action up to ~23 hours in mouse behavioral models. Plasma half-life specifically isn't characterized in published peer-reviewed PK studies. The 23-hour figure is single-source, single-lab. Routes used in published studies are intraperitoneal in mouse models; no human PK study. BBB penetration is inferred from CNS pharmacodynamic effects in rodents. Bioavailability isn't 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.
Pre-filled with a typical PE-22-28 setup. Edit any field — the draw updates live.
Insulin syringe — 100 units = 1 mL
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StackTrax doesn't 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, draw 0.2 mL (20 units).
Storage: lyophilized stable at room temperature short-term, refrigerate longer-term. Reconstituted: refrigerate, use within 28 days. Full protocol in the Bacteriostatic Water guide.
No published human safety data on PE-22-28. No FAERS, EudraVigilance, or Yellow Card entries. From rodent data: 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 is the most important practical caveat — SSRIs already amplify serotonergic tone, TREK-1 inhibition adds another layer, and stacking PE-22-28 with an SSRI is a double-mechanism serotonergic intervention with no safety data. 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.
| Compound | Difference from PE-22-28 |
|---|---|
| BDNF | 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 mechanism. |
| 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. Sometimes lumped with PE-22-28 in vendor catalogs but unrelated. |
| SSRIs (fluoxetine, sertraline, escitalopram) | Reuptake inhibitors. PE-22-28 doesn't inhibit SERT; amplifies serotonergic firing via TREK-1 inhibition. Stacking uncharacterized. |
| Ketamine / esketamine | NMDA antagonist; rapid-acting via glutamatergic / synaptogenesis. Both are "fast-acting" candidates but mechanistically distinct. |
| Dihexa | HGF/c-Met positive modulator. 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; failed two Phase 2 MDD trials. Different mechanism and trajectory. |
| Semax / Selank | Russian-origin nootropic peptides. Different mechanisms (BDNF/NGF and GABAergic). PE-22-28 is from a French academic lab. |
| MIF-1 | D2 PAM mechanism. Different target. |
PE-22-28 is a research peptide not approved by the FDA for human use. It is sold only as a research chemical, and StackTrax does not endorse or facilitate personal use.
Quality varies enormously among research-chemical suppliers. At minimum, look for:
StackTrax’s preferred partner NextGen Peptides does not currently carry PE-22-28in their catalog, which is why you don’t see a direct purchase link here. Other major research-chemical suppliers carry it; we don’t specifically recommend one for this compound.
Build your protocol, log every dose, monitor your body's response, and get reminders so you never miss a dose.
Start Tracking FreePE-22-28 (also written PE 22-28) is a heptapeptide with sequence Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR). It is the C-terminal tail of spadin, which is itself a 17-amino-acid fragment of the propeptide region of sortilin (NTSR3, encoded by SORT1). Mechanism is inhibition of the TREK-1 (KCNK2) two-pore-domain potassium channel. Despite widespread vendor framing, PE-22-28 is NOT a BDNF fragment and has nothing to do with BDNF or TrkB signaling.
No — and this is a factual error that the existing StackTrax encyclopedia and most vendor descriptions repeat. PE-22-28 is the C-terminal tail of spadin (a sortilin propeptide fragment), and its mechanism is TREK-1 K2P potassium channel inhibition. PubMed searches for "PE 22-28 AND BDNF" and for the literal sequence GVSWGLR both return zero records. BDNF is a 119-amino-acid neurotrophin protein that signals via TrkB — unrelated by sequence and by mechanism. Do not conflate them.
TREK-1 (KCNK2) is a member of the K2P two-pore-domain potassium channel family — a "leak" K+ channel that is constitutively open and hyperpolarizing. It is 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 — the genetic anchor for the antidepressant hypothesis. The proposed mechanism for PE-22-28: bind and inhibit TREK-1, reduce K+ leak in serotonergic neurons, increase firing, enhance serotonergic tone in mood-relevant circuits.
Sortilin (NTSR3 / SORT1) is an endogenous receptor protein whose propeptide region is cleaved during processing. Spadin is the 17-amino-acid fragment of that propeptide, identified by the Borsotto / Lazdunski group at IPMC Sophia Antipolis (France) as a TREK-1 inhibitor with antidepressant-like activity (Mazella et al. 2010, PMID 20405001). PE-22-28 is the C-terminal heptapeptide of spadin, designed as a shorter and simpler analog (Djillani et al. 2017, PMID 28955242). Same target, same mechanism, smaller peptide.
No. Zero human clinical trial data exist for PE-22-28. The entire PE-22-28-specific primary literature is a single 2017 paper from one French academic lab (Djillani et al., Front Pharmacol). All subsequent work cites it. The often-quoted "0.12 nM IC50" and "23-hour duration" figures both trace to that single rodent source with no independent replication. The TREK-1 antidepressant TARGET is well-anchored by multiple independent groups, but PE-22-28 as the specific way to drug it has not been validated outside that one lab.
No. PE-22-28 has never been FDA approved or EMA approved. No NDA, no IND on file. Sold as a research chemical. WADA 2026: not on the prohibited list by name, and the cleanest reading is that only the S0 catch-all (non-approved substances) applies — PE-22-28 does not plausibly fall under S2 (no growth-factor-mimetic angle, no peptide-hormone classification).
StackTrax does not endorse PE-22-28 use, and no published human trial exists. Community dosing extrapolates Djillani 2017 mouse data to human weight: 200–500 mcg per spray intranasally, 1–2 sprays per day, or 100–500 mcg per day subcutaneously. Some users go every-other-day given the claimed long duration. Cycles are typically 2–6 weeks. None of these figures is anchored to any published human trial.
No published human safety data, no FAERS, EudraVigilance, or Yellow Card entries. Rodent data showed it was generally well-tolerated in mouse models. The most important practical caveat is SSRI stacking — SSRIs already amplify serotonergic tone, TREK-1 inhibition adds another layer, and combining PE-22-28 with an SSRI is a double-mechanism serotonergic intervention with no safety data. Cardiac: TREK-1 has roles in cardiac repolarization, and 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 is uncharacterized — discontinue ahead of any procedure.
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StackTrax guides cover peptides and compounds that are not FDA-approved for the uses discussed. The dosing, reconstitution, and safety information is compiled from published research and community protocols for educational purposes only.
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