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PreclinicalVendors pendingFacts verified · 2026-05-25

PE-22-28

Also known as spadin fragment, pe 22-28 · Wikipedia

PE-22-28 is a 7-amino-acid C-terminal fragment of spadin (Gly-Val-Ser-Trp-Gly-Leu-Arg), itself derived from the propeptide of the sortilin neurotensin receptor, developed by the Mazella group (CNRS, France) as a novel antidepressant candidate. It selectively inhibits TREK-1 (KCNK2) two-pore-domain potassium channels with sub-nanomolar affinity, producing rapid-onset antidepressant-like effects and neurogenesis enhancement in rodent models. PE-22-28 has improved plasma stability and longer behavioral duration than parent spadin. The entire human evidence base is zero - no clinical trials in humans have been completed.

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Mechanism of action

PE-22-28 is a 7-amino-acid C-terminal fragment of spadin (Gly-Val-Ser-Trp-Gly-Leu-Arg), itself derived from the propeptide of sortilin. It is a high-affinity selective inhibitor of TREK-1 (KCNK2) two-pore-domain potassium channels with IC50 ~0.

PE-22-28 is a 7-amino-acid C-terminal fragment of spadin (Gly-Val-Ser-Trp-Gly-Leu-Arg), itself derived from the propeptide of sortilin. It is a high-affinity selective inhibitor of TREK-1 (KCNK2) two-pore-domain potassium channels with IC50 ~0.12 nM, more potent than parent spadin (IC50 ~40-60 nM) (Veyssiere et al., PubMed 28955242). TREK-1 blockade depolarizes serotonergic dorsal raphe neurons and enhances 5-HT neurotransmission, producing rapid-onset antidepressant-like effects in rodent forced-swim and novelty-suppressed feeding tests without ketamine-style dissociation. PE-22-28 also enhances hippocampal neurogenesis and synaptogenesis (PSD-95 expression) after short subchronic dosing. Behavioral effect duration extends to ~23 h in rodents versus ~7 h for spadin.

Pharmacokinetic properties

Half-life

~90-120 minutes plasma (substantially improved over parent spadin's ~8 min); behavioral effects reportedly up to 23 hours in animal models

Routes

subcutaneous · intranasal

Bioavailability

Designed with serine modification that blocks aminopeptidase cleavage. Oral bioavailability is poor (peptide). No validated human PK data.

Amino-acid sequence

Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR)

Use & research dosing

Antidepressant ResearchNeurogenesis

No human clinical dose has been established. Rodent antidepressant studies typically use around 100 mcg/kg subcutaneously, often delivered as a 4-day subchronic regimen. Self-experimentation protocols circulating in the research-chemical channel commonly report 200-500 mcg/day subcutaneously, often cycled 4-6 weeks. These protocols extrapolate directly from rodent forced-swim and novelty-suppressed feeding data with no validated human PK, dose-finding, or efficacy work to support them. Research framing only.

Research-use framing only. SavePeptides sells nothing for human consumption. Doses above reflect reported research / self-experimentation ranges, not clinical recommendations.

Editorial perspective

TREK-1 inhibition is a genuinely novel antidepressant target with mechanistic interest, but the entire human evidence base is zero clinical trials. All efficacy claims extrapolate from rodent forced-swim, novelty-suppressed feeding, and chronic-stress models from the Mazella group (CNRS / IPMC, France). PE-22-28 was designed as a stability-improved fragment of spadin; the serine residue blocks aminopeptidase cleavage. Human translation has not been attempted in a published trial.

— SavePeptides editorial desk · last updated 2026-05-25

Cautions & contraindications

Before researching this compound, note:

  • No human safety or efficacy trials - entirely preclinical evidence base
  • Theoretical serotonin-syndrome risk if combined with SSRIs, SNRIs, MAOIs, or other serotonergic drugs
  • Pregnancy and lactation safety unknown
  • Not FDA-approved; research chemical only
  • Long-term effects of TREK-1 inhibition in humans are unstudied
  • Vendor sterility, identity, and purity are highly variable
  • Theoretical cardiovascular effects from TREK-1 inhibition (TREK-1 is expressed in cardiac and vascular tissue)
  • Theoretical pain-perception effects (TREK-1 is implicated in mechanosensation and nociception)

Research foundation

The papers behind the page.

  1. [01]https://pubmed.ncbi.nlm.nih.gov/28955242/
  2. [02]https://pubmed.ncbi.nlm.nih.gov/20405001/

Facts verified

2026-05-25

Confidence

low

What this means

  • no human clinical trials
  • preclinical-only evidence (rodent behavioral models)
  • theoretical serotonergic interaction risk

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