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.
Also known as: TREK-1 Channel Blocker, Shortened Spadin Analog, Mini-Spadin
Overview
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
- Depression Research
- Neurogenesis / Cognitive
- Anxiety Research
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.
Research Protocols Injectable
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Preclinical Antidepressant Studies (Mouse) | 3-4 mcg/kg | Once daily | Subcutaneous |
| Preclinical Oral Studies (Mouse) | 1 mg/kg | Once daily | Subcutaneous |
| Research Protocol (Human Equivalent - Theoretical) | 50-100 mcg | Once daily | Subcutaneous |
| Research Protocol (Conservative) | 100-200 mcg | Once daily | Subcutaneous |
Research protocols from published literature — not dosing recommendations.
Peptide Interactions
- SSRIs (Fluoxetine, Sertraline) — Monitor Combination: Both target serotonergic pathways via different mechanisms. Fluoxetine also weakly inhibits TREK-1. Theoretical additive effects - monitor for excessive serotonergic activity
- Semax / NA-Semax — Potentially Synergistic: Both support neurogenesis and cognitive function via different mechanisms. Semax acts through BDNF/NGF; PE-22-28 via TREK-1 inhibition. Complementary nootropic stack
- Selank — Synergistic: Both have anxiolytic and neuroprotective properties. Selank modulates GABA; PE-22-28 blocks TREK-1 potassium channels. Different mechanisms for anxiety/mood support
- Dihexa — Potentially Synergistic: Both promote neurogenesis and synaptic plasticity through different pathways. Dihexa acts via HGF/c-Met; PE-22-28 via TREK-1/5-HT enhancement. Complementary neuroplasticity targets
- Cerebrolysin — Compatible: Both support neuroplasticity and neuroprotection. Cerebrolysin provides neurotrophic factors; PE-22-28 enhances 5-HT transmission and neurogenesis via TREK-1 blockade
- BPC-157 — Compatible: BPC-157 has shown neuroprotective effects and dopamine system modulation. Different mechanisms from PE-22-28's TREK-1 action. No contraindications identified
- Potassium Channel Modulators — Use Caution: Other drugs affecting potassium channels could have additive or antagonistic effects. PE-22-28 is selective for TREK-1 but caution warranted with K+ channel drugs
- MAOIs — Avoid Combination: PE-22-28 increases serotonergic neurotransmission. Combining with MAOIs could theoretically increase serotonin syndrome risk. No clinical data - avoid combination
Peptide Instructions Injectable
Supplies:
- PE-22-28 lyophilized powder (typically 5-10 mg vials)
- Bacteriostatic water for injection
- Insulin syringes (29-31 gauge)
- Alcohol prep pads
- Sterile work surface
- Refrigerator for storage (2-8°C)
How to Reconstitute Injectable
- 1Remove PE-22-28 vial from refrigerator and allow to reach room temperature
- 2Clean the rubber stopper with alcohol swab
- 3Determine reconstitution volume (e.g., 2 mL BAC water for 10 mg vial = 5 mg/mL or 5000 mcg/mL)
- 4Draw bacteriostatic water into syringe slowly
- 5Inject BAC water slowly down the inside wall of the vial - do not spray directly on powder
- 6Gently swirl vial until powder is completely dissolved - do not shake
- 7Solution should be clear and colorless
- 8Label vial with reconstitution date and concentration
- 9Store reconstituted solution in refrigerator at 2-8°C
- 10Use within 4-6 weeks of reconstitution
What to Expect Injectable
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.
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.
Community Insights
PE-22-28 (Mini-Spadin) should be stored at Lyophilized: refrigerate 2-8°C or -20°C for long-term; Reconstituted: refrigerate, use within 4-6 weeks.
Molecular Information
References
- 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
- Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels
- Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin
- Role of TREK-1 in Health and Disease, Focus on the Central Nervous System
- Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity
- Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design
- Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype
- Role of TREK-1 in Health and Disease - CNS Focus
- Fighting Against Depression with TREK-1 Blockers
- Spadin: A Sortilin-Derived Peptide Targeting TREK-1 Channels
- TREK-1 Deletion Results in Depression-Resistant Phenotype
Research reference only. Not medical advice.