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Neuropeptide

PE-22-28

Also known as: Shortened spadin analog

A synthetic 7-amino-acid peptide derived from spadin (not spexin — a common mix-up in secondary sources), designed as a TREK-1 potassium channel antagonist and studied for antidepressant-like activity in a mouse model.

Educational content, not advice. Compiled from information publicly available on the internet; it may contain inaccuracies and was not written or reviewed by medical professionals. Use it as a starting point for your own research, verify against primary sources, and see our full disclaimer.

A note on naming

PE-22-28 is frequently described in vendor and secondary sources as related to "spexin." That appears to be a naming mix-up: the peptide it's actually derived from, per the primary literature, is spadin — a peptide cleaved from the sortilin propeptide, structurally and biologically unrelated to spexin (a different, separately studied appetite-regulating peptide). We're flagging this explicitly because it's an easy mistake to carry forward, and it changes what mechanism and prior literature is actually relevant.

Overview

PE-22-28 is a synthetic 7-amino-acid peptide, a shortened analog of spadin engineered for improved stability and potency. It's studied as an antagonist of the TREK-1 potassium channel, a target implicated in mood regulation.

Proposed Mechanism of Action

By inhibiting TREK-1 channel activity, PE-22-28 is proposed to affect neuronal excitability in circuits relevant to mood — this is the same target class explored by spadin itself, with PE-22-28 developed specifically to improve on spadin's pharmacological properties (better channel inhibition, better in vivo stability).

Research Context

The cited study compared several shortened spadin analogs, including PE-22-28, for TREK-1 inhibition potency, metabolic stability, and antidepressant-like activity in a corticosterone-induced mouse model of depression (a standard preclinical depression model). PE-22-28 was highlighted as a leading candidate among the analogs tested.

Limitations of the Current Evidence

  • This is an animal model of depression, not a human trial — preclinical antidepressant models are useful for mechanism screening but have historically shown mixed translation to human clinical efficacy across many compound classes, not specific to this peptide.
  • The "spexin" naming confusion circulating in secondary sources means it's worth independently verifying any other claims you encounter about PE-22-28 against primary sources, since some of that confusion likely extends to misattributed mechanism or effect claims as well.

Cited Studies

  • Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity

    Djillani A, Pietri M, Moreno S, Heurteaux C, Mazella J, Borsotto M · Frontiers in Pharmacology · 2017

    Animal study (mouse, corticosterone-induced depression model)View source →

Last updated August 1, 2026