PE-22-28 (Mini-Spadin)
TREK-1 Channel Blocker | Shortened Spadin Analog
PE-22-28, also known as Mini-Spadin, is a synthetic heptapeptide derived from positions 22-28 of the parent peptide Spadin. Spadin itself originates from the propeptide (PE) released during the maturation of sortilin/neurotensin receptor-3 (NTSR3). PE-22-28 is a potent and selective antagonist of TREK-1 (TWIK-Related Potassium Channel-1), a two-pore domain potassium channel implicated in depression, neuroprotection, and pain modulation. With an IC50 of 0.12 nM, PE-22-28 demonstrates approximately 300-500 fold greater affinity for TREK-1 compared to full-length Spadin. Preclinical research shows rapid antidepressant effects within 4 days, accompanied by neurogenesis and synaptogenesis in the hippocampus - significantly faster than conventional SSRIs.
Daily dose
50-200 mcg
Frequency
Once daily
Cycle length
4-8 weeks
Storage
2-8°C
Key benefits
Rapid antidepressant effects (4 days preclinical), neurogenesis, synaptogenesis, enhanced 5-HT transmission, ~23 hour duration, 300-500x more potent than Spadin
How it works
Selective TREK-1 potassium channel blocker (IC50 0.12 nM). Increases serotonergic neuron firing in dorsal raphe nucleus, triggers CREB phosphorylation and BDNF expression, induces hippocampal neurogenesis.
Dosage protocols
Goal
Research Protocol
Dose
50-200 mcg · Once daily
Route
Subcutaneous
Research indications
mood
cognitive
anxiety
neuroprotection
Administration
Interactions
Safety notes
NOT FDA-approved - research compound only
No human clinical trials conducted
Preclinical safety profile favorable (no cardiac, seizure, or pain effects)
Theoretical serotonin interaction risk with MAOIs
Long-term human safety unknown
Research studies
Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1
Frontiers in Pharmacology 2020 | Mechanism of action study
Revealed Spadin and analogs specifically antagonize arachidonic acid-mediated TREK-1 activation via allosteric mechanism. This selective inhibition may explain favorable side effect profile compared to non-specific K+ channel blockers.
View study →Role of TREK-1 in Health and Disease - CNS Focus
Frontiers in Physiology 2019 | Comprehensive review | Multiple disease states
Review establishing TREK-1's role in depression, neuroprotection, pain, and anesthesia. TREK-1 is highly expressed in prefrontal cortex, hippocampus, and amygdala - regions critical for mood and memory. Supports TREK-1 blockers as novel therapeutic approach.
View study →Fighting Against Depression with TREK-1 Blockers
Pharmacology & Therapeutics 2019 | Review of Spadin research
Comprehensive review of TREK-1 as depression target and Spadin development. Highlighted rapid onset of action (4 days vs weeks for SSRIs), neurogenesis induction, and favorable safety profile in preclinical studies.
View study →Shortened Spadin Analogs Display Better TREK-1 Inhibition
Frontiers in Pharmacology 2017 | In vitro and in vivo studies | Mice models
Demonstrated PE-22-28 has IC50 of 0.12 nM vs 40-60 nM for Spadin (300-500x improvement). Duration of action extended to ~23 hours vs 7 hours for Spadin. Induced neurogenesis after 4-day treatment with BrdU+ cells nearly doubling compared to controls.
View study →Spadin: A Sortilin-Derived Peptide Targeting TREK-1 Channels
PLOS Biology 2010 | Original spadin discovery | Multiple depression models
Foundational study identifying Spadin as first endogenous TREK-1 blocker with antidepressant properties. Demonstrated 4-day treatment induced CREB phosphorylation and hippocampal neurogenesis comparable to chronic SSRI treatment.
View study →TREK-1 Deletion Results in Depression-Resistant Phenotype
Nature Neuroscience 2006 | TREK-1 knockout mice | Behavioral and electrophysiology
Landmark study showing TREK-1 knockout mice display depression-resistant phenotype in 5 behavioral tests, increased 5-HT neurotransmission in dorsal raphe nucleus, and reduced stress-induced corticosterone. Established TREK-1 as valid antidepressant target.
View study →