PE-22-28
Also known as: PE 22-28, PE22-28, shortened spadin analogue, spadin-derived peptide
3 notable studies · 3 references
TLDR
PE-22-28 is a seven-amino-acid spadin-derived peptide that potently inhibits the TREK-1 potassium channel and produces rapid antidepressant-like effects in preclinical models, but controlled human efficacy, pharmacokinetic, and safety evidence is currently lacking.
Research Supports
- Developed and studied as a potential rapid-acting antidepressant strategy via TREK-1 inhibition
- Investigated for potency and selectivity at the TREK-1 potassium channel
- Studied, as part of the spadin family, for links to serotonergic neuron firing
- Investigated for effects on hippocampal neurogenesis and synaptic plasticity
- Related shortened spadin peptides studied in stroke-recovery models
Observations Reported in Research
- PE-22-28 inhibited human TREK-1 in HEK cells with an IC50 of about 0.12 nM, vs 40-60 nM for spadin (Veyssière et al., 2017)
- Parent peptide spadin increased serotonergic neuron firing and produced antidepressant-like effects across mouse behavioral tests (Mazella et al., 2010)
- Spadin treatment increased hippocampal CREB phosphorylation and neurogenesis after several days (Mazella et al., 2010)
- Stabilized spadin analogues retained antidepressant-like effects and increased neurogenesis in a separate study (Béraud-Dufour et al., 2014)
- No controlled human administration evidence for PE-22-28 itself was identified
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Synthetic heptapeptide; spadin-derived TREK-1 potassium-channel inhibitor; experimental antidepressant peptide
PE-22-28 is a seven-amino-acid peptide derived from spadin, an endogenous sortilin-derived peptide investigated for antidepressant-like activity. Its principal experimental target is TREK-1 (KCNK2), a two-pore-domain potassium channel involved in regulation of neuronal excitability. The basic research story is: Sortilin precursor to sortilin propeptide to spadin / PE 12-28 to shortening and optimization to PE-22-28. Researchers developed PE-22-28 because the original spadin peptide showed interesting antidepressant-like effects but relatively poor in-vivo stability. The shortened peptide was reported to inhibit TREK-1 much more potently than spadin and produce rapid antidepressant-like effects in mice. PE-22-28 does not have established human antidepressant efficacy. The evidence remains preclinical.
What Is PE-22-28?
Spadin is a 17-amino-acid peptide derived from the maturation pathway of sortilin, also known as neurotensin receptor-3. Researchers discovered that spadin interacts with and inhibits TREK-1. TREK-1 became interesting because mice lacking the TREK-1 gene display behavioral characteristics resembling antidepressant treatment responses. The original spadin peptide, however, had limited stability. Researchers examined its degradation products and identified a much shorter sequence, PE-22-28, containing only seven amino acids. This shorter peptide retained and substantially increased TREK-1 inhibitory activity.
What Are Researchers Studying?
Depression
PE-22-28 was specifically developed as a potential rapid-acting antidepressant strategy. In mouse behavioral models, shortened spadin analogues produced antidepressant-like responses after short treatment periods. This generated interest because conventional monoamine-based antidepressants often require substantially longer treatment before full clinical effects emerge. Rapid antidepressant-like behavior in mice is not the same as a rapid antidepressant treatment in humans. No established clinical trials demonstrate that PE-22-28 treats major depressive disorder in people.
TREK-1 inhibition
TREK-1 is a member of the K2P two-pore-domain potassium-channel family. These channels help regulate the resting electrical properties of neurons. Inhibiting TREK-1 can increase neuronal excitability and alter circuits involved in mood regulation. In electrophysiology experiments, PE-22-28 inhibited human TREK-1 expressed in HEK cells with an IC50 around 0.12 nM, compared with approximately 40-60 nM for spadin under the same experimental conditions. That is a striking increase in experimental potency. It does not tell us the effective or safe exposure in humans.
Serotonergic signaling
TREK-1 biology intersects with serotonin signaling. Earlier spadin experiments demonstrated increased firing of serotonergic neurons in the dorsal raphe nucleus following TREK-1 blockade. Other experimental work suggests TREK-1 blockade can interact with 5-HT1A receptor signaling. That provides a plausible connection between TREK-1 inhibition and mood-related neural circuitry without making PE-22-28 simply another serotonin-reuptake inhibitor.
Neurogenesis
Spadin and related analogues have been associated with increased hippocampal neurogenesis in rodents. The original spadin experiments found increased CREB phosphorylation and neurogenesis after several days of treatment. Optimized analogues have also demonstrated neurogenesis-related effects. This contributed to the hypothesis that TREK-1 inhibition could produce downstream neural adaptations associated with antidepressant activity. Rodent hippocampal neurogenesis is not established human antidepressant efficacy.
Synaptogenesis
The broader spadin research program has linked TREK-1 inhibition with changes in synaptic plasticity and formation of neuronal connections. These findings are interesting because depression research increasingly involves neural plasticity rather than solely neurotransmitter concentrations. PE-22-28 should not yet be described as a clinically established neuroplasticity peptide.
Stroke and neurological recovery
Related shortened spadin peptides have also been investigated in mouse stroke models. Mini-spadin produced dose-dependent effects on TREK-1 and was associated experimentally with improvements in motor, cognitive, and post-stroke depression measures. This is related-family evidence rather than proof that PE-22-28 itself improves human stroke recovery.
How Does It Work?
The primary proposed mechanism is: PE-22-28 to TREK-1 inhibition to altered neuronal potassium conductance to increased neuronal excitability to changes in serotonergic and neural-plasticity pathways to antidepressant-like behavioral effects in experimental animals. TREK-1 is not simply a depression receptor. It is an ion channel with broader physiological roles involving neuronal excitability, pain, temperature, anesthesia, neuroprotection, and cardiovascular physiology. That is why selectivity and safety matter.
What Does the Research Show?
Human research
There is no established controlled human administration evidence for PE-22-28 as an antidepressant. Human evidence exists around major depressive disorder, sortilin biomarkers, TREK-1 biology, and conventional antidepressants interacting with TREK-1. Sortilin-derived peptides have also been detected in human serum, with research investigating altered concentrations in depression. Finding a related endogenous peptide in humans does not establish that administering synthetic PE-22-28 is safe or therapeutic.
Animal research
This is the primary efficacy evidence. Research involving spadin and optimized derivatives has examined depression-like behavior, neurogenesis, serotonergic signaling, synaptogenesis, stroke recovery, and post-stroke depression. The results support TREK-1 as an interesting experimental antidepressant target.
In-vitro research
This is particularly strong for the target mechanism. Patch-clamp experiments demonstrated potent inhibition of TREK-1 by PE-22-28, with substantially greater potency than the original spadin peptide. Researchers have also examined modifications to the peptide termini and their effects on TREK-1 inhibition and stability.
Notable Studies
Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity
animalResearchers analyzed spadin degradation products and developed shortened derivatives, including the seven-amino-acid PE-22-28. PE-22-28 inhibited TREK-1 substantially more potently than spadin, with an IC50 of approximately 0.12 nM versus 40-60 nM, and displayed improved experimental stability and antidepressant-like activity.
Limitations: Cellular and animal experiments only. Potency at an ion channel does not establish antidepressant efficacy or safety in humans.
View publication →Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design
animalResearchers demonstrated that spadin binds and inhibits TREK-1, increases firing of serotonergic neurons, and produces antidepressant-like responses across multiple mouse behavioral tests. Several days of treatment also increased hippocampal CREB phosphorylation and neurogenesis.
Limitations: This study examined spadin, the parent peptide, rather than PE-22-28. Results establish the biological foundation from which PE-22-28 was developed but should not be presented as direct PE-22-28 evidence.
View publication →Retroinverso Analogs of Spadin Display Increased Antidepressant Effects
animalResearchers developed stabilized spadin analogues designed to improve affinity and duration. Selected analogues retained antidepressant-like effects and increased hippocampal neurogenesis following short treatment.
Limitations: Different spadin derivatives were studied rather than PE-22-28 specifically. The findings support the broader optimization strategy, not direct human efficacy.
View publication →What We Still Don't Know
Whether PE-22-28 has antidepressant effects in humans; human pharmacokinetics; human bioavailability; whether it crosses the human blood-brain barrier adequately; safe human exposure; long-term safety; whether rapid antidepressant-like effects translate clinically; effects on suicidality; interactions with antidepressants; effects in bipolar-spectrum disorders; seizure-related effects during chronic exposure; cardiovascular effects during chronic exposure; whether neurogenesis contributes meaningfully to its behavioral effects; whether research-market PE-22-28 matches the peptide used experimentally.
Related Compounds
Recent publications
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Sources & References
- Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity
- Mazella J, et al. Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design
- Béraud-Dufour S, et al. Retroinverso Analogs of Spadin Display Increased Antidepressant Effects
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