PE-22-28

Research Overview

PE-22-28 serves as a valuable research tool for investigating rapid antidepressant mechanisms, TREK-1 potassium channel function, and neurogenesis-dependent mood regulation in laboratory settings. This synthetic heptapeptide was identified through studies of sortilin, a sorting receptor involved in neurotrophin trafficking and neuronal function. The sortilin propeptide region containing PE-22-28 sequence demonstrates high affinity for TREK-1 channels, providing researchers with a specific tool for studying this channel’s role in depression and neuroplasticity.

The peptide’s discovery resulted from investigations into novel antidepressant mechanisms beyond monoamine modulation. TREK-1 potassium channels contribute to neuronal excitability and have emerged as potential antidepressant targets. PE-22-28’s selective TREK-1 blocking activity and rapid behavioral effects in animal models make it valuable for dissecting depression mechanisms and identifying alternative therapeutic approaches.

Laboratory studies investigate PE-22-28’s effects on neuronal membrane properties, hippocampal neurogenesis (cell proliferation, survival, differentiation), synaptic plasticity, and depression-related behaviors in preclinical models. Research demonstrates rapid-onset antidepressant-like effects (within 4 hours) in validated behavioral paradigms, contrasting with conventional antidepressants requiring chronic administration.

Molecular Characteristics

Complete Specifications:

• Chemical Name: PE-22-28, Spadin
• Molecular Weight: ~800 Da
• Parent Protein: Sortilin Propeptide (amino acids 22-28)
• Peptide Classification: TREK-1 channel antagonist peptide
• Target: TREK-1 (TWIK-related K+ channel, KCNK2)
• Appearance: White to off-white lyophilized powder
• Solubility: Water, DMSO, appropriate buffer systems
• Binding Affinity: High-affinity TREK-1 interaction (nM range)

The peptide’s 7-amino acid structure represents the minimal active sequence for TREK-1 channel blocking activity. Specific amino acid residues within this sequence are critical for channel recognition and functional blockade. Structure-activity relationship studies have identified key residues essential for TREK-1 binding affinity and selectivity over other two-pore domain potassium channels.

Mechanism of Action:
PE-22-28 functions as a selective TREK-1 channel antagonist. TREK-1 channels are background potassium channels contributing to resting membrane potential and neuronal excitability. By blocking TREK-1 activity, PE-22-28 causes membrane depolarization, increased neuronal firing, and enhanced synaptic plasticity. This mechanism differs fundamentally from monoamine-targeting antidepressants, providing alternative research approaches to mood regulation.

Pharmacokinetic Profile in Research Models

PE-22-28 pharmacokinetic characterization in preclinical research reveals properties relevant for experimental design:

Administration and CNS Penetration:

• Routes investigated: Intravenous, intraperitoneal, intracerebroventricular
• Blood-brain barrier penetration: Documented with appropriate formulation
• Brain regional distribution: Hippocampus, prefrontal cortex (regions relevant to depression)
• Peak brain concentrations: 30-90 minutes post-systemic administration

Pharmacodynamics:

• Rapid behavioral effects: Antidepressant-like activity within 4 hours
• Duration of action: Effects persist for hours to days depending on model
• TREK-1 blockade kinetics: Sustained channel inhibition documented
• Neurogenesis effects: Enhanced hippocampal cell proliferation observed 2-7 days post-administration

Metabolism Considerations:

• Peptidase susceptibility: Moderate stability, optimization studies ongoing
• Modified analogs: Investigations into metabolically stable versions
• Optimal formulation: Vehicle selection impacts bioavailability and CNS penetration

These pharmacokinetic/pharmacodynamic characteristics enable diverse research protocols investigating acute antidepressant mechanisms, neurogenesis time courses, and channel-dependent vs. neurogenesis-dependent behavioral effects.

Research Applications

TREK-1 Potassium Channel Research

PE-22-28 serves as a selective research tool for investigating TREK-1 channel function:

• Channel Pharmacology Studies: Investigation of TREK-1 blocking kinetics, selectivity, and mechanism
• Electrophysiological Research: Patch-clamp studies examining membrane potential and excitability modulation
• Channel Structure-Function: Research on TREK-1 activation mechanisms (pH, mechanical stretch, lipids)
• Channel Distribution Studies: Investigation of TREK-1 expression patterns in brain regions and neuronal subtypes
• Channel-Behavior Relationships: Studies correlating TREK-1 function with behavioral phenotypes

Research protocols employ electrophysiology (whole-cell patch-clamp, field recordings), genetic manipulations (TREK-1 knockout models), and pharmacological comparisons with other TREK-1 modulators to characterize PE-22-28’s channel effects.

Rapid Antidepressant Mechanism Investigation

Laboratory studies investigate PE-22-28’s rapid antidepressant-like properties:

• Behavioral Pharmacology: Investigation using forced swim test, tail suspension test, learned helplessness paradigms
• Temporal Analysis: Studies examining onset kinetics and duration of antidepressant-like effects
• Dose-Response Relationships: Research establishing effective concentration ranges in behavioral models
• Stress Resilience Studies: Investigation of stress-protective effects and resilience mechanisms
• Comparative Pharmacology: Studies comparing PE-22-28 with conventional SSRIs, ketamine, and other rapid-acting compounds

Experimental protocols correlate PE-22-28’s molecular/cellular effects (TREK-1 blockade, neurogenesis, synaptic changes) with behavioral outcomes to establish mechanism-behavior relationships.

Adult Hippocampal Neurogenesis Research

PE-22-28 enables investigation of neurogenesis-mood relationships:

• Cell Proliferation Studies: Analysis of neural progenitor division using BrdU, EdU labeling
• Neuronal Differentiation: Investigation of progenitor fate determination and neuronal maturation
• Survival and Integration: Research on long-term survival of adult-born neurons and synaptic integration
• Neurogenesis-Behavior Correlations: Studies examining relationships between hippocampal neurogenesis and antidepressant-like effects
• Neurogenesis Requirement: Investigations using irradiation or genetic ablation to test neurogenesis necessity for PE-22-28’s behavioral effects

Research protocols span acute to chronic timelines, employing immunohistochemistry (DCX, NeuN, BrdU), confocal microscopy, stereology, and behavioral testing to characterize PE-22-28’s neurogenesis effects.

Synaptic Plasticity Research

Research applications extend to synaptic mechanism investigation:

• Long-Term Potentiation: Studies examining LTP magnitude and duration in hippocampus
• Dendritic Spine Analysis: Research on spine density, morphology, and dynamics
• Synaptic Protein Expression: Investigation of synaptophysin, PSD-95, and scaffolding protein modulation
• Neurotransmitter Systems: Studies on glutamatergic, GABAergic, and monoaminergic transmission
• BDNF Pathway Research: Investigation of brain-derived neurotrophic factor expression and TrkB signaling

Laboratory protocols combine electrophysiology, molecular analysis, and structural imaging to characterize PE-22-28’s synaptic plasticity effects and relationships to behavioral outcomes.

Stress Response Research

PE-22-28 provides a tool for investigating stress neurobiology:

• HPA Axis Studies: Research on hypothalamic-pituitary-adrenal axis regulation and cortisol modulation
• Stress-Induced Changes: Investigation of molecular, cellular, and behavioral stress responses
• Stress Resilience Mechanisms: Studies on protective pathways preventing stress-induced pathology
• Chronic Stress Models: Research in chronic unpredictable stress, social defeat, and other chronic stress paradigms
• Glucocorticoid Receptor Modulation: Investigation of GR expression and function in stress-responsive brain regions

Experimental models examine PE-22-28’s effects on stress-induced behavioral deficits, hippocampal atrophy, and molecular stress markers to understand stress-antidepressant interactions.

Depression Model Research

Laboratory studies investigate PE-22-28 across diverse depression models:

• Behavioral Despair Models: Forced swim test, tail suspension test
• Learned Helplessness: Inescapable shock paradigms and subsequent testing
• Chronic Stress Models: Chronic unpredictable mild stress (CUMS), chronic social defeat
• Anhedonia Models: Sucrose preference, intracranial self-stimulation
• Genetic Models: Selective breeding for depression-like phenotypes, genetic manipulations

Comprehensive behavioral batteries assess PE-22-28’s effects on multiple depression-related dimensions: behavioral despair, anhedonia, anxiety, cognitive function, social interaction.

Laboratory Handling and Storage Protocols

Lyophilized Powder Storage:

• Store at -20°C to -80°C in original sealed vial
• Protect from light exposure and moisture
• Desiccated storage environment required
• Stability data: 12+ months at -20°C under proper conditions

Reconstitution Guidelines:

• Reconstitute with sterile water, DMSO (for stock solutions), or appropriate buffer
• Add solvent slowly down vial side to minimize foaming
• Gentle swirling motion recommended (avoid vigorous shaking)
• Allow complete dissolution before use (2-5 minutes)
• For in vivo studies, prepare appropriate vehicle formulations for BBB penetration

Reconstituted Solution Storage:

• Short-term storage: 4°C for up to 7 days in appropriate buffer
• Long-term storage: -20°C in aliquots to avoid freeze-thaw cycles
• Single-use aliquots strongly recommended
• Avoid repeated freeze-thaw cycles (maximum 2-3 cycles)
• DMSO stock solutions: Store at -20°C, protected from light

Special Handling Considerations:
PE-22-28 requires careful formulation for in vivo CNS studies. Vehicle selection and administration route significantly impact brain penetration and efficacy. Consult literature for validated delivery protocols.

Quality Assurance and Analytical Testing

Each PE-22-28 batch undergoes comprehensive analytical characterization:

Purity Analysis:

• High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS): ≥95% purity
• Analytical methods optimized for peptide verification
• Multiple detection methods for accurate purity assessment

Structural Verification:

• Mass spectrometry: Confirms molecular weight (~800 Da)
• Peptide sequencing: Verifies amino acid sequence accuracy
• Peptide content determination: Quantifies actual peptide content by weight

Functional Verification:

• TREK-1 channel activity assays where applicable
• Bioactivity confirmation in relevant cellular systems
• Quality control beyond analytical purity to ensure biological function

Contaminant Testing:

• Bacterial endotoxin: <5 EU/mg (LAL method)
• Heavy metals: Below detection limits per USP standards
• Residual solvents: Within acceptable limits
• Water content: Karl Fischer titration

Documentation:

• Certificate of Analysis (COA) provided with each batch
• Third-party analytical verification available upon request
• Stability data documented for recommended storage conditions
• Batch-specific QC results traceable by lot number

Research Considerations

Experimental Design Factors:

Researchers should consider several factors when designing PE-22-28 experiments:

1. Behavioral Timing: PE-22-28 demonstrates rapid effects (4-24 hours) compared to conventional antidepressants (2-3 weeks). Design behavioral testing accordingly.

2. Neurogenesis Timelines: Cell proliferation effects occur within days, but functional integration of new neurons requires weeks. Different endpoints require different experimental timelines.

3. Delivery Methods: CNS penetration varies with administration route and vehicle. Optimize delivery for specific experimental needs.

4. Model Selection: Choose depression models appropriate for research questions (acute behavioral despair vs. chronic stress-induced changes).

5. Control Comparisons: Include conventional antidepressants (SSRIs), novel compounds (ketamine), and TREK-1 knockout controls where appropriate.

Mechanism Investigation:

PE-22-28’s mechanisms involve multiple interconnected processes:

• Direct TREK-1 channel blockade and membrane depolarization
• Enhanced neuronal excitability and firing rates
• Increased hippocampal neurogenesis (proliferation and survival)
• Synaptic plasticity enhancement (LTP, dendritic spines)
• BDNF expression and neurotrophin signaling
• HPA axis modulation and stress response normalization

Multi-level experimental approaches combining electrophysiology, molecular biology, neurogenesis quantification, and behavioral assessment provide comprehensive mechanistic insights.

Compliance and Safety Information

Regulatory Status:
PE-22-28 is provided as a research chemical for in-vitro laboratory studies and preclinical research only. This product has not been approved by the FDA for human therapeutic use, dietary supplementation, or medical applications.

Intended Use:

• In-vitro electrophysiology studies
• In-vivo preclinical research in approved animal models
• Laboratory investigation of depression mechanisms
• Academic and institutional research applications

NOT Intended For:

• Human consumption or administration
• Therapeutic treatment or diagnosis
• Dietary supplementation
• Veterinary therapeutic applications without appropriate oversight

Safety Protocols:
Researchers should follow standard laboratory safety practices when handling PE-22-28:

• Use appropriate personal protective equipment (lab coat, gloves, safety glasses)
• Handle in well-ventilated areas or fume hood
• Follow institutional biosafety guidelines
• Dispose of waste according to local regulations for biological/chemical waste
• Consult material safety data sheet (MSDS) for additional safety information

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