PE-22-28

PE-22-28 is a seven-amino-acid fragment of the sortilin-derived propeptide (PE), built from the degradation products of the natural TREK-1 blocker spadin ¹. TREK-1 is a background potassium channel that helps set the resting electrical state of neurons. Blocking it makes neurons slightly more excitable and has been linked to antidepressant-like effects in animal models ².

Against the human TREK-1 channel, PE-22-28 has an IC50 of 0.12 nM, about 400-fold more potent than spadin (40–60 nM), and its action lasts up to roughly 23 hours versus roughly 7 hours for spadin ¹. In mice, four days of treatment reduced immobility in the forced-swim test, shortened feeding latency in the novelty-suppressed feeding test, and increased hippocampal neurogenesis ¹.

Research has focused on major depression, treatment-resistant depression, neurogenesis, and post-stroke recovery, with secondary studies on insulin-producing cells and inflammation ⁵. No interventional trial in humans has been published. The only human evidence follows the naturally occurring parent peptide as a blood biomarker in depression and stroke cohorts ⁹.

As a potassium leak channel, TREK-1 lets potassium ions leave neurons, keeping the cell membrane hyperpolarized and less likely to fire. PE-22-28 blocks this channel, depolarizing neurons and increasing excitability ¹. Spadin, the parent peptide, raised the firing rate of serotonin-producing neurons in the dorsal raphe by 113% in vivo ².

This electrical change activates growth and plasticity signaling. Spadin and related analogs turn on MAPK and PI3K pathways, increase CREB phosphorylation and brain-derived neurotrophic factor (BDNF), and raise synaptic markers including PSD-95 and synapsin ¹. Blocking TREK-1 also appears to amplify serotonin 5-HT1A receptor signaling through a shared PKA-CREB-BDNF pathway ¹⁵.

Dose direction is an unusual feature. In a mouse stroke study, a very low dose (0.03 mcg/kg intraperitoneal) activated TREK-1 and was neuroprotective, while a higher dose (3 mcg/kg) inhibited the channel and produced antidepressant-like effects ¹³. Which part of this curve applies to any human dose is unknown.

Additional actions include reduced inflammatory signals in microglia and astrocytes via TNF-alpha, NF-kB, and NLRP3 pathways ²⁰, and beta-cell depolarization that potentiates insulin secretion while protecting beta cells from inflammatory stress ¹¹. No human pharmacokinetic study exists; the compound's activity window is inferred to be around 23 hours from rodent work ¹.

Rapid antidepressant-like behavior

In mice, four days of PE-22-28 reduced forced-swim immobility and shortened novelty-suppressed feeding latency ¹. In a chronic unpredictable mild stress rat model, TREK-1 blockers reversed depressive-like behavior at least one week earlier than fluoxetine and restored hippocampal neurogenesis with chronic dosing ⁵.

Neurogenesis and synapse formation

Spadin-class compounds increased BDNF, PSD-95, synapsin, and mature dendritic spines, and PE-22-28 induced neurogenesis after only four days ¹. These changes are the main mechanistic basis for the proposed mood and cognition benefits.

Stroke recovery and post-stroke depression

In a mouse focal ischemia model, mini-spadin showed a dose-dependent switch: a low dose activated TREK-1 for neuroprotection, while a higher dose blocked TREK-1 and prevented post-stroke depression and motor/cognitive deficits ¹³. This evidence is preclinical only.

Insulin-producing cells

TREK-1 blockade depolarized pancreatic beta cells and potentiated glucose-stimulated insulin secretion in mice ¹². Sortilin-derived peptides also protected beta cells from IL-1 beta-induced death and promoted proliferation in vitro ¹¹.

Human biomarker data

No efficacy trial has tested PE-22-28. Serum levels of the naturally occurring parent propeptide correlated with depression scores in 204 chronic-stroke patients and rose after electroconvulsive therapy only in treatment responders ⁹. These observational results support the pathway's human relevance but not the peptide's effects.

Evidence limits

Claims for cognition, motivation, and stress resilience in healthy people remain community-reported. The strongest direct evidence is rodent behavioral and in vitro electrophysiology ¹.

All published efficacy studies of PE-22-28 use systemic injection in rodents. In the mouse stroke model, mini-spadin was given intraperitoneally at 0.03 mcg/kg once daily for seven days in the neuroprotective phase, or 3 mcg/kg four days per week in the post-stroke depression phase ¹³. Spadin and related analogs reached measurable antidepressant-like effects after four days of daily treatment ¹.

Because no human dose-finding work exists, community research protocols supply the only practical schedules. Common community patterns use 200–500 mcg subcutaneously once daily, or 100–200 mcg intranasally twice daily, for 4–8 week cycles. Practitioner consensus favors a low starting dose around 100–250 mcg once daily, titrated by mood response rather than body weight. These doses have never been tested in a controlled human study and fall well above a simple allometric translation of the mouse antidepressant dose ¹³.

Morning administration is the usual community default. The rationale is that TREK-1 blockade raises serotonin neuron firing in the dorsal raphe by 113% in rodents, which could be undesirable close to sleep ². The roughly 23-hour activity window supports once-daily dosing ¹.

Published rodent treatment windows run from four days to three weeks without desensitization in the studies examined ¹. Community cycles are typically 4–8 weeks on with 2–4 weeks off; no tachyphylaxis or withdrawal data exist.

PE-22-28 is handled as a lyophilized powder that is reconstituted before research use. The default diluent is bacteriostatic water containing 0.9% benzyl alcohol; sterile water is an alternative for single-use preparations. The diluent is added slowly against the vial wall, and the vial is swirled gently rather than shaken or foamed.

For storage, the lyophilized powder is kept at −20°C for long-term stability and at 2–8°C for short-term use, protected from light and moisture. Once reconstituted, the solution should be kept refrigerated at 2–8°C and used within 14–30 days when bacteriostatic water is used, or within about 7 days with sterile water. Cloudy or particulate solutions should be discarded.

The shortened sequence of PE-22-28 improves in vivo stability relative to spadin, and the endogenous parent propeptide is measurable in human serum, which supports peptide stability in biological matrices ¹. The calculator below converts vial size, diluent volume, and target dose into draw volumes for research use.

All interaction data for PE-22-28 come from rodent and cell-line studies. No human interaction trial has been published.

• SSRIs: Fluoxetine is itself a TREK-1 blocker ². In a rat stress model, TREK-1 blockers reversed depressive-like behavior faster than fluoxetine, and in a mouse decompression model combining spadin with fluoxetine improved survival ⁵. The expected direction is additive antidepressant and neuronal-excitability effect.
• 5-HT1A agonists: 5-HT1A receptor activation appears synergistic with TREK-1 blockade through PKA-CREB-BDNF signaling ¹⁵.
• 5-HT4 agonists: Animal data do not support combining these with PE-22-28. Adding a 5-HT4 agonist to spadin produced a paradoxical collapse of dorsal raphe serotonin firing ¹⁹.
• mGluR2/3 modulators: Spadin's effect on serotonin firing depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors ¹⁹.
• TREK-1 openers: Agents such as BL-1249, ML-335, and RNE28 directly oppose TREK-1 blockade. TREK-1 activation is also downstream of opioid analgesia ²⁷.
• Insulin secretagogues and GLP-1 receptor agonists: Spadin potentiated glucose-stimulated insulin secretion in mice ¹². Additive glucose-lowering effects are theoretically possible.
• Quercetin: This supplement activates TREK-1 in part through PKC-related signaling, and spadin reversed its observed effects ³⁰. High-dose quercetin may oppose the peptide's mechanism.
• Fish oil: DHA-driven TREK-1 activation appears insensitive to spadin, so fish oil is unlikely to cancel the peptide but preserves some channel tone ¹⁶.
• Cardiovascular and pulmonary agents: Rodent data showed no blockade of cardiac IKr or IKs currents and no blood-pressure changes after 3 weeks of spadin ⁷. However, TREK-1 inhibition depolarizes human pulmonary artery smooth muscle and trabecular meshwork cells, so pulmonary hypertension and glaucoma are theoretical cautions ³¹.

PE-22-28 has no published human combination studies, so stack evidence is mechanistic or community-based.

• With GLP-1 receptor agonists: Both TREK-1 blockade and incretin drugs increase beta-cell insulin output, which could mean additive glucose lowering ¹¹. Glucose monitoring is sensible in research settings.
• With BPC-157: This is a common community pairing for mood and neuroinflammation. No direct combination data exist. Mechanistically, TREK-1 blockade reduces NLRP3 and IL-1 beta output in immune cells, which overlaps with BPC-157's anti-inflammatory profile ²².
• With Semax or Selank: Community protocols pair these for cognitive and mood research. Direct data are absent; the expectation is additive monoaminergic and BDNF-related signaling ⁶.
• With other TREK-1 blockers: Fluoxetine and similar blockers would be expected to act additively. Combination regimens in research settings are typically titrated slowly because PE-22-28's action lasts about 23 hours ¹.
• TREK-1 activators: Analgesic TREK-1 openers act in the opposite direction and are not compatible with PE-22-28 in the research literature ²⁷.

PE-22-28 is not approved by the FDA or EMA for any indication, and no registered clinical trial has administered it to humans ¹. Its published characterization comes from mouse behavioral models and in vitro electrophysiology ¹. The only human data concern blood levels of the endogenous parent propeptide, not the synthetic peptide ⁹.

• United States: PE-22-28 is not scheduled under the Controlled Substances Act. It remains an unapproved new drug, so interstate sale for human use is not lawful under federal drug law.
• European Union and United Kingdom: No marketing authorization exists; the substance is outside licensed medicines pathways.
• Australia: Not on the ARTG, and the Personal Importation Scheme is not available for research-only-labeled peptides.
• Sport: PE-22-28 is not named on the WADA Prohibited List. Because it is a fragment of an endogenous propeptide, distinguishing administered peptide from natural cleavage products in anti-doping analysis is not currently documented ¹.

PE-22-28 has no human safety data. The following picture comes from rodent and cell-line studies of PE-22-28, spadin, and mini-spadin.

• Cardiac: Three weeks of spadin did not block cardiac IKr or IKs currents or change systolic pressure or pulse in mice ⁷.
• Metabolic: TREK-1 blockade potentiates glucose-stimulated insulin secretion and protects beta cells, which points toward possible glucose lowering ¹¹. Chronic blockade or TREK-1 knockout also increased adipocyte differentiation, lipid accumulation, and high-fat-diet fat gain in mice ²⁴.
• Pain: Early studies reported no pain-related worsening ⁷, but a later rat study found that spadin increased formalin-induced flinching and long-lasting mechanical allodynia and hyperalgesia ²⁵. New or worsening pain in research participants should be treated as potentially drug-related.
• Seizure and stroke: TREK-1 deletion increases seizure sensitivity, but spadin did not worsen kainate-induced seizures in the examined rodent model ⁷. The low-dose versus high-dose channel direction adds uncertainty in acute stroke ¹³.
• Immune and inflammatory effects: TREK-1 blockade reduced NLRP3, IL-1 beta, microglial, and astrocyte inflammatory signaling in preclinical models ²¹. The systemic immune consequences in humans are unknown.
• Serotonergic combinations: The 5-HT4 depolarization-block risk and SSRI overlap caution from animal studies mean serotonergic combinations deserve close attention ¹⁹.
• Pregnancy, breastfeeding, pediatric, and elderly use: No human data exist; research has not established safe conditions for these groups.
• Community reports: Injection-site reactions, mild headache, and transient restlessness are the most commonly described events in community use. Long-term human risk is unstudied.