PE-22-28

Overview

PE-22-28 is a 7-amino-acid synthetic analog of spadin, a peptide fragment (residues 22-28) of the 44-aa propeptide (PE) released during post-translational maturation of sortilin (the neurotensin receptor-3). It is studied in preclinical models as a fast-acting antidepressant that works by selectively blocking the TREK-1 two-pore potassium channel. There is no established use for hair growth — that is a separate compound and the two should not be confused.

Mechanism of Action

PE-22-28 is a highly selective antagonist of the TREK-1 (KCNK2) two-pore-domain potassium channel, with reported in vitro IC50 near 0.12 nM — roughly 300–500× more potent than the parent spadin peptide (IC50 ~40–60 nM). TREK-1 is enriched in serotonergic neurons of the dorsal raphe nucleus; blocking it depolarizes these neurons and enhances 5-HT transmission to limbic targets. In rodents, TREK-1 blockade also increases hippocampal neurogenesis and synaptic markers (PSD-95, BDNF), which is hypothesized to underlie its rapid-onset antidepressant signature.

Research Summary

Mazella, Borsotto and colleagues (Nice, France) first identified spadin (Mazella et al., 2010) and subsequently developed shortened PE 22-28 analogs with markedly improved TREK-1 affinity and in vivo half-life (Djillani et al., 2017). In mouse antidepressant assays (forced swim, tail suspension, novelty-suppressed feeding), acute or 4-day intraperitoneal dosing of PE 22-28 analogs at ~3–4 μg/kg produced antidepressant-like effects comparable to chronic SSRI treatment, and oral dosing at 1 mg/kg by gavage was also active. The modified G/A-PE 22-28 analog extended duration of action to ~21–23 hours. Chronic dosing did not cause the cardiac or seizure liabilities seen with non-selective K-channel blockers. No human clinical trials have been completed; all efficacy data to date is preclinical.

Dosing Information

Reported Side Effects

• Unknown in humans — no clinical safety data
• Rodent studies did not report overt toxicity at effective doses
• Theoretical: potassium channel modulation could affect cardiac repolarization at higher exposures
• Injection site reactions (typical of SubQ peptides)

Research References

• Shortened spadin analogs display better TREK-1 inhibition, in vivo stability, and antidepressant activity (2017)
• Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design (2010)
• Fighting against depression with TREK-1 blockers: past and future. A focus on spadin (2019)