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PE-22-28

Cognitive & Neurological · ['Spadin analog PE 22-28', 'shortened spadin analog']

A synthetic seven-amino-acid analog of the endogenous peptide spadin that inhibits the TREK-1 potassium channel, studied in rodent models for antidepressant-like effects and hippocampal neurogenesis.

🔬 Research use only — not for human or veterinary use. K4 Elite does not provide dosing instructions.
Research Level
Emerging Research
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PE-22-28 is a synthetic heptapeptide (seven amino acids) engineered as a shortened analog of spadin, a naturally occurring peptide cleaved from the propeptide of sortilin (neurotensin receptor-3) during its processing in the Golgi apparatus. Spadin was identified in the early 2010s as an endogenous molecule with antidepressant-like activity that acts by blocking the TREK-1 potassium channel.

Spadin's short duration of action and relatively modest receptor affinity limited its usefulness as a research tool. PE-22-28 was designed by Djillani, Mazella, Borsotto and colleagues to improve TREK-1 binding, extend in vivo stability, and prolong duration of action while retaining the core pharmacology.

No single PubChem compound CID is available for PE-22-28 in this reference, so the identifier field is left blank. All information is drawn from published preclinical research and is provided for research and reference use only.

PE-22-28 inhibits TREK-1, a two-pore-domain (K2P) potassium channel. TREK-1 normally allows potassium to leak out of neurons, contributing to a hyperpolarized, less excitable state. By blocking this leak in serotonin-associated brain regions, PE-22-28 is proposed to make relevant neurons easier to depolarize, which the authors frame as its antidepressant-like mechanism.

Downstream, short treatment courses in rodents were reported to increase hippocampal neurogenesis and markers of synaptic plasticity, which the authors suggested could relate to a faster onset of mood-related effects than conventional serotonergic agents in those models.

  • TREK-1 channel inhibition: Electrophysiology and binding studies characterizing PE-22-28 as a more potent TREK-1 blocker than spadin.
  • Antidepressant-like behavior: Rodent behavioral paradigms (forced swim test, novelty-suppressed feeding) evaluating mood-related endpoints.
  • Hippocampal neurogenesis: Studies reporting increased neurogenesis after short treatment courses in mice.
  • In vivo stability / analog design: Structure-activity work on shortened spadin analogs to improve stability and duration.
  • TREK-1 in neuroprotection: Broader interest in TREK-1 modulation for mood and neuroprotection research.
📋 How published studies were conducted — a research reference summarizing study designs from the literature. This is not usage, dosing, or administration guidance. K4 Elite does not provide dosing instructions; determining any research protocol is the sole responsibility of the qualified researcher.

Djillani et al., Frontiers in Pharmacology (2017): The core study screened shortened spadin analogs and identified PE-22-28 as the standout, reporting substantially stronger TREK-1 inhibition, improved in vivo stability, and antidepressant-like behavior in mice using the forced swim and novelty-suppressed feeding tests. Reported for reference only.

Neurogenesis reports (same research line): Follow-up work from the Mazella/Borsotto group reported that short treatment courses increased hippocampal neurogenesis in rodents, framed as a possible basis for a faster behavioral response than conventional SSRIs. These are animal-model observations.

Spadin foundational studies: Earlier work characterizing spadin as an endogenous TREK-1 inhibitor with antidepressant-like activity provided the rationale for the PE-22-28 analog series. Any doses in these studies are experimental parameters, not recommendations.

Combinations examined in the research literature. Descriptive only — not a recommendation to combine compounds.

SSRIs / serotonergic agentsNeutral
PE-22-28 acts via TREK-1 rather than serotonin transporters; comparative behavioral studies use SSRIs as reference agents.
Other TREK-1 modulatorsCompatible
Shares the same channel target; used as comparators in electrophysiology research.
SpadinCompatible
PE-22-28 is a stability-optimized analog of spadin with the same proposed mechanism.
General anesthetics acting on K2P channelsCaution
Some anesthetics modulate two-pore potassium channels; a theoretical interaction noted for research awareness only.

References are being compiled for this entry.

What is PE-22-28 derived from?
It is a shortened synthetic analog of spadin, a natural peptide cleaved from the sortilin propeptide that inhibits the TREK-1 potassium channel.
How does PE-22-28 work in studies?
It blocks the TREK-1 potassium channel, which in rodent models is associated with antidepressant-like behavior and increased hippocampal neurogenesis.
Why is the PubChem CID blank?
No single verified PubChem compound record was identified for PE-22-28 at the time of writing, so the identifier is intentionally left empty rather than guessed.
Is there human clinical data?
No. The available evidence is from rodent studies and in vitro electrophysiology; there are no published human clinical trials in this reference.
Is PE-22-28 approved for use?
No. PE-22-28 is a research-use-only compound. It is not approved for human or veterinary use, and this entry is for reference only, not medical advice or a usage recommendation.
Disclaimer: This profile summarizes published preclinical and laboratory research for reference only. It is not medical advice and makes no claim of safety or efficacy in humans. Determining any research protocol is the sole responsibility of the qualified researcher. Products are sold strictly for in-vitro research and have not been evaluated by the FDA.