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Overview
What is PE-22-28 (Mini-Spadin)?
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.
Key Benefits
Rapid antidepressant-like effects (4 days in preclinical models), hippocampal neurogenesis, synaptogenesis (PSD-95 increase), CREB activation, enhanced serotonergic neurotransmission, potential neuroprotection, extended duration of action (~23 hours)
Mechanism of Action
PE-22-28 selectively blocks TREK-1 potassium channels with IC50 of 0.12 nM. TREK-1 inhibition increases neuronal excitability in the dorsal raphe nucleus, enhancing serotonin (5-HT) firing rate and neurotransmission. This triggers downstream CREB phosphorylation, BDNF expression, and hippocampal neurogenesis. Unlike SSRIs that take weeks, these effects manifest within 4 days in animal models.
Molecular Information
Weight
773.89 Da
Length
7 amino acids
Type
Linear heptapeptide
Amino Acid Sequence:
Gly-Val-Ser-Trp-Gly-Leu-Arg (GVSWGLR)
* Shortened analog of Spadin (PE 12-28, 17 amino acids). Represents the C-terminal fragment responsible for TREK-1 binding activity. Analog G/A-PE 22-28 (glycine-to-alanine substitution) shows similar or improved activity
Research Indications
Depression Research
Primary research focus. Preclinical studies show rapid antidepressant effects in forced swim test, tail suspension test, learned helplessness, and novelty-suppressed feeding models. Acts faster than SSRIs with 4-day efficacy window
Neurogenesis Enhancement
PE-22-28 nearly doubles hippocampal BrdU-positive (newborn) cells after 4-day treatment. 85% of new cells are neuronal precursors (DCX-positive), indicating genuine neuroplasticity
Research Protocols
Disclaimer
These are commonly discussed research protocols and not medical advice. Consult a healthcare provider before use.
Timing
PE-22-28 has ~23 hour duration of action in animal studies, supporting once-daily administration. Morning dosing is common but specific timing may not be critical.
Peptide Interactions
How to Reconstitute
Important
Always use bacteriostatic water (BAC). Sterile technique is essential.
Remove PE-22-28 vial from refrigerator and allow to reach room temperature
Clean the rubber stopper with alcohol swab
Determine reconstitution volume (e.g., 2 mL BAC water for 10 mg vial = 5 mg/mL or 5000 mcg/mL)
Draw bacteriostatic water into syringe slowly
Inject BAC water slowly down the inside wall of the vial - do not spray directly on powder
Gently swirl vial until powder is completely dissolved - do not shake
Solution should be clear and colorless
Label vial with reconstitution date and concentration
Store reconstituted solution in refrigerator at 2-8°C
Use within 4-6 weeks of reconstitution
Quality Indicators
White lyophilized powder
Should appear as white to off-white powder or fluffy cake in sealed vial
Clear, colorless reconstituted solution
After reconstitution, solution must be completely clear with no particles or cloudiness
Certificate of Analysis (COA) available
Research peptide should have third-party testing showing >98% purity and identity confirmation via HPLC/MS
Proper cold chain shipping
Should arrive cold-packed; extended room temperature exposure may degrade peptide
Research compound status
PE-22-28 is not FDA-approved. Available only as research chemical. Quality varies by supplier
Cloudy, discolored, or particles visible
Any turbidity, yellow/brown color, or floating particles indicates degradation
Clumped or sticky powder
Indicates moisture exposure and likely degradation - do not use
What to Expect
- Day 1-4: Preclinical data suggests measurable effects within 4 days; subjective effects in humans unknown
- Week 1-2: Based on mechanism, expect neuroplasticity processes to be underway
- Week 2-4: If effective, mood and cognitive improvements may become noticeable
- Week 4-8: Sustained use allows full neurogenic effects to develop
- Note: No human clinical trials - all timing based on animal model extrapolation
- Effects are research-context only; individual responses in humans are unknown
Side Effects & Safety
- NOT FDA-approved - research compound only with no human clinical trials
- All safety data is from preclinical (animal) studies
- Preclinical studies show no effects on TREK-2, TRAAK, TASK-1, TRESK, or cardiac hERG channels - suggests cardiac safety
- Animal studies showed no pain hypersensitivity, seizures, or cardiac dysfunction
- Spadin showed no effects on sleep-wake cycle or memory at tested doses in rats
- Theoretical serotonin syndrome risk if combined with MAOIs or high-dose SSRIs - avoid combination
- Long-term safety in humans completely unknown
- Not recommended during pregnancy or breastfeeding (no safety data)
- May affect other undiscovered targets - exercise caution
- Start with lowest effective dose; do not exceed research protocol ranges
References
Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1
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 (opens in new tab) →Role of TREK-1 in Health and Disease - CNS Focus
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 (opens in new tab) →Fighting Against Depression with TREK-1 Blockers
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 (opens in new tab) →Quick Start Guide
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