What Is PE-22-28?
PE-22-28 is a synthetic 7-amino-acid peptide analog of Spadin — itself a naturally occurring peptide cleaved from the propeptide of NTSR3/sortilin. Spadin was identified as a natural blocker of TREK-1, a two-pore domain potassium channel expressed in the brain implicated in depression, stress sensitivity, and memory formation. PE-22-28 is an optimized analog with improved stability and potency for TREK-1 inhibition.
TREK-1 as a Depression Target
TREK-1 is a background potassium channel that, when open, hyperpolarizes neurons and reduces their excitability. Pharmacological evidence suggests TREK-1 overactivity contributes to depression-like states: TREK-1 knockout mice are resistant to both depression and helplessness and show enhanced spatial memory. TREK-1 inhibition therefore represents an antidepressant mechanism entirely distinct from monoamine reuptake inhibition.
Antidepressant and Cognitive Research
PE-22-28 has demonstrated rapid antidepressant-like effects in mouse models — with onset within hours, unlike conventional antidepressants requiring weeks. It also stimulates hippocampal neurogenesis (increasingly recognized as important for sustainable antidepressant response) and shows improvements in hippocampal synaptic plasticity and memory task performance — suggesting applications beyond depression to cognitive enhancement and memory disorders.
Quick Reference
Member reference tables summarize the compound's research parameters.
Research Indications
Research Protocols
As reported in cited literature and research-community logs (see Research Citations below), not a personal dosing recommendation.
This member section describes parameters reported in the research literature.
Peptide Interactions
This member section summarizes reported compound interactions and evidence limitations.
Reported Research Time Points
This member section summarizes reported research time points.
Safety Notes
Included for harm-reduction awareness only, in the event this compound is encountered outside its labeled research use. Inclusion here does not imply RUO Codes endorses, recommends, or instructs human use.
This member section discusses research safety considerations and uncertainties.
Quality Indicators
Research Citations
- 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, 2017, Front Pharmacol - Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design
Mazella J, Pétrault O, Lucas G, et al., 2010, PLoS Biol - Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype
Heurteaux C, Lucas G, Guy N, et al., 2006, Nat Neurosci - Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin
Djillani A, Mazella J, Heurteaux C, Borsotto M, 2019, Pharmacol Ther - Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels
Vivier D, Bhella G, Bhella A, et al., 2020, Front Pharmacol - Role of TREK-1 in Health and Disease, Focus on the Central Nervous System
Bockenhauer D, Zilberberg N, Bhella A, 2019, Front Physiol - Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
Peretti D, Smith HL, et al., 2023, Neurochem Res