PE-22-28 is an experimental brain-research peptide — a shortened, more stable piece of spadin, a natural peptide studied for mood and recovery pathways. Rather than acting like a classic neurotrophin or "BDNF mimetic," it works by blocking a potassium "leak" channel called TREK-1 that helps set how easily neurons fire. It is not an approved antidepressant or any medical treatment, and the science so far is almost entirely in animals and lab dishes. It is sold only as a research reagent.
A shortened sortilin/spadin-derived heptapeptide investigated as a potent, selective TREK-1 / KCNK2 inhibitor (IC₅₀ ≈ 0.12 nM, vs spadin's 40–60 nM), with preclinical antidepressant-like, hippocampal-neurogenesis, post-stroke-recovery, and beta-cell-survival signals. It was engineered from spadin blood-degradation products to improve potency and in-vivo stability. Its clinical use is not established: human PK, dosing, efficacy, and safety are all lacking, and it is a laboratory research reagent, not an approved drug.
PE-22-28 — GVSWGLR (Gly-Val-Ser-Trp-Gly-Leu-Arg; C₃₅H₅₅N₁₁O₉, MW 773.89 Da, CAS 1801959-12-5, PubChem CID 165437303) — the smallest spadin fragment retaining spadin-like TREK-1 inhibition. On hTREK-1/HEK cells (patch-clamp) it showed better specificity and affinity than spadin (IC₅₀ 0.12 nM vs 40–60 nM), induced hippocampal neurogenesis after a 4-day treatment, increased PSD-95 synaptogenesis, and extended action duration up to ~23 h (G/A-PE-22-28 / biotin-G/A analogs) vs spadin's ~7 h. Evidence is rodent/cellular only.
0.12 nMTREK-1 IC₅₀ · vs spadin 40–60 nM
~23 hAction duration (analogs) · vs spadin ~7 h
PreclinicalRodent / cellular only · no human trial
PE-22-28 is best understood as a precision ion-channel tool: the smallest, most potent fragment of spadin, engineered to block the TREK-1 potassium channel that gates neuronal excitability in mood and memory circuits. It is frequently mislabeled a "BDNF mimetic" — it is not. Its lineage is sortilin/spadin and its target is TREK-1/KCNK2. The biology is compelling in rodents and cells, but there is no human trial, no validated dose, and only research-reagent status.
🧠
Primary use case
Mood research
A research-stage antidepressant / post-stroke / neurorecovery peptide candidate — not a clinical therapy. Grade C.
🔑
Mechanism headline
TREK-1 block
A potent TREK-1 / KCNK2 inhibitor, IC₅₀ ≈ 0.12 nM — far more potent than parent spadin. Grade C/P.
📊
Strongest evidence tier
Animal / cellular
The strongest direct evidence is animal and cellular, not human interventional evidence. Grade C.
🧬
Distinctive signal
Fast neurogenesis
Induced hippocampal neurogenesis after only a 4-day treatment, with increased PSD-95 synaptogenesis. Grade C.
💉
Dose status
No human dose
Rodent work used low µg/kg dosing (~3 µg/kg IP); any human calculator must be labeled speculative/research-only. Grade D.
♻️
Engineering win
Stability
Designed from spadin's blood-degradation products; analogs extend action to ~23 h vs spadin's ~7 h. Grade C.
⚠️
Key risk
CNS activation
Theoretical neuropsychiatric, seizure/excitability, and cardiac/GI uncertainty from broad TREK biology. Grade D/P.
🏛️
Regulatory status
Reagent only
No approved human indication; laboratory research reagent only. Grade D.
02 · Mechanism of action
How PE-22-28 acts on the TREK-1 channel.
PE-22-28's mechanism is unusually specific for a research peptide: it inhibits TREK-1 (KCNK2), a two-pore-domain "leak" potassium channel that helps set the resting excitability of neurons in mood and memory circuits. Blocking TREK-1 is linked to antidepressant-like effects, serotonergic firing changes, and rapid hippocampal neurogenesis in rodents. Every node below is preclinical (Grade C/P) — the channel biology is well established, but the human translation is hypothesis.
Grade C/P
🔑
1 · TREK-1 / KCNK2 modulation
PE-22-28 is designed to influence a potassium "leak" channel that helps set neuronal excitability.
Clinical significance: TREK-1 channels regulate neuronal membrane potential, stress-response signaling, mood circuits, pain, and ischemia responses. TREK-1 is broadly relevant across CNS function. Inhibiting it raises neuronal excitability in targeted circuits, the proposed antidepressant lever.
Molecular detail: TREK-1 is a two-pore-domain (K2P) background K⁺ channel; PE-22-28 is the shortest efficient spadin-derived inhibitor. Listed as a potent TREK-1 inhibitor, IC₅₀ ≈ 0.12 nM; on hTREK-1/HEK patch-clamp it out-performed spadin (0.12 nM vs 40–60 nM), and N-/C-terminal modifications could preserve or abolish channel activity without changing affinity.
Grade P
🎛️
2 · State-dependent / allosteric antagonism
Rather than simply plugging the channel, spadin-family peptides may prevent certain activation states.
Clinical significance: State-dependent modulation could explain CNS effects without broadly shutting down all TREK-related functions — a selectivity advantage. Spadin did not behave as a simple direct blocker under all conditions.
Molecular detail: Spadin selectively antagonized arachidonic-acid activation of TREK-1, likely through an allosteric / state-dependent mechanism rather than simple pore block. Extrapolation of this exact mechanism to PE-22-28 is a reasonable hypothesis, not a proven identity.
Grade C
🌧️
3 · Antidepressant-like behavioral signaling
In rodent models, spadin-family peptides reduced depression-like behavior.
Clinical significance: TREK-1 genetic deletion or pharmacologic inhibition is linked to antidepressant-like effects in animals. Spadin is a sortilin-derived peptide targeting rodent TREK-1 with antidepressant-like activity; PE-22-28 was developed to improve on it.
Molecular detail: In the forced-swim test, spadin-analog-treated mice showed reduced immobility; after a 4-day sub-chronic treatment, PE-22-28 reduced latency to eat in the novelty-suppressed-feeding test — two complementary antidepressant-like paradigms. Established in rodents; not established in humans.
Grade C/P
⚡
4 · Serotonergic circuit activation hypothesis
PE-22-28 may influence mood circuits partly by changing serotonin-neuron firing.
Clinical significance: TREK-1 blockade in dorsal-raphe / serotonergic systems is one proposed antidepressant pathway for spadin-family compounds. TREK-1 modulation is linked to serotonergic firing and antidepressant-like behavior.
Molecular detail: TREK-1 is expressed in serotonergic neurons; inhibiting it is proposed to increase serotonin transmission through interplay with mGluR2/3 and mPFC circuitry. The link between TREK-1 modulation and serotonergic firing underlies the antidepressant hypothesis; direct human serotonergic effects of PE-22-28 are not established.
PE-22-28 has been studied for brain recovery after ischemic injury in animals.
Clinical significance: In rodent ischemia models, sortilin-derived peptides improved recovery markers including hippocampal neurogenesis and reduced motor/cognitive deficits. Pietri et al. reported protective effects on stroke recovery and post-stroke depression.
Molecular detail: BrdU labeling showed increased dentate-gyrus neurogenesis after 4-day treatment (prominent for G/A-PE-22-28), consistent with increased PSD-95 (synaptogenesis). Neurogenesis in this region is associated with antidepressant response across drug classes, though causality remains debated. Animal-only.
Grade P/C
🩸
6 · Beta-cell survival / CREB signaling
PE-22-28 may protect pancreatic beta cells in stress models — a branch beyond the brain.
Clinical significance: Sortilin-derived peptides have been studied in beta-cell survival under inflammatory stress. PE and derivatives promoted beta-cell survival through calcium/CaM-kinase/CREB-related signaling in preclinical systems. This is not a diabetes therapy claim.
Molecular detail: The proposed cascade is membrane depolarization → intracellular Ca²⁺ rise → CaM-kinase → CREB phosphorylation → pro-survival signaling under cytokine stress. Daziano et al. mapped this CREB pathway in beta cells — preclinical only, mechanistically distinct from the CNS TREK-1 story.
L3 · Cascade (CNS branch)
Proposed CNS signaling cascade
🧪 PE-22-28
preclinical
→
🔑 TREK-1 block
IC₅₀ ≈ 0.12 nM
→
⚡ ↑ Excitability
↓ K⁺ leak
→
🌱 5-HT + neurogenesis
PSD-95 ↑
→
🌧️ AD-like behavior
rodent endpoints
L3 · Spadin lineage
From sortilin propeptide to PE-22-28
Molecule
What it is
TREK-1 IC₅₀
Action duration
Sortilin propeptide
Endogenous source of spadin
—
—
Spadin (PE 12-28)
17-residue parent peptide
40–60 nM
~7 h
PE-22-28
7-residue minimal fragment
0.12 nM
improved
G/A-PE-22-28
Modified analog
potent
~21 h
Biotin-G/A-PE-22-28
Labeled analog
potent
~23 h
L3 · Why TREK-1 selectivity matters
Selectivity rationale & the two mechanistic branches
PE-22-28 has no approved human dosing. The models below are a speculative research-layer for an atlas calculator, not medical recommendations. Human pharmacokinetics, safety, bioavailability, therapeutic window, and validated cycles are all unknown — the only real numbers come from rodent behavioral work (~3 µg/kg IP) and in-vitro potency. Treat the route panels and bands as hypothesis-modeling scaffolds, clearly labeled as such.
No approved human dosing exists
PE-22-28 is listed as a laboratory research reagent, not an approved drug, with no labeled indication. All dose bands and calculator outputs on this page are for research math and hypothesis modeling only — not treatment guidance. As an unapproved experimental peptide, athlete use is high-risk under WADA S0 (non-approved substances); the 2026 list is in force. Anyone considering use for depression or stroke recovery should be under qualified medical care, not self-experimenting.
What is actually known
PE-22-28 was selected as a shortened spadin analog with high TREK-1 potency (IC₅₀ 0.12 nM) and preclinical antidepressant-like activity at ~3 µg/kg IP in rodents; analog action duration extends to ~23 h vs spadin's ~7 h. There is no human half-life, Cmax, Tmax, bioavailability, or clearance. The "~7 h / ~23 h" figures are rodent stability observations, not human pharmacokinetics, and must not be converted into a human dosing schedule.
Subcutaneous research model
Speculative · no validated human protocol
Grade D/P
Starting dose
0.5 µg/kg/day — conservative research extrapolation below rodent active ranges.
Escalation
Increase only if no adverse CNS, sleep, mood, cardiovascular, or GI signals occur.
Not for pregnancy, lactation, seizure disorder, unstable psychiatric disease, active suicidality, uncontrolled cardiovascular disease, or unsupervised combination with antidepressants. Basis: rodent low-µg/kg work; human model is speculative. Grade D/P.
Dose bands · research-only
Global dose-band table (calculator bands, not clinical doses)
Band
µg/kg/day
70 kg example
Basis · grade
Low
0.5
35 µg/day
Below rodent active range · D/P
Standard
1.0
70 µg/day
Hypothesis band · D/P
High
2.0
140 µg/day
Upper speculative · D/P
Animal-reference
3.0–4.0 µg/kg IP
not valid human scaling
Rodent forced-swim context · C
Weight-band scaffold
Weight-band interpolation (calculator scaffold, not a prescription)
Body weight
Low 0.5 µg/kg
Standard 1.0 µg/kg
High 2.0 µg/kg
55 kg
27.5 µg
55 µg
110 µg
65 kg
32.5 µg
65 µg
130 µg
75 kg
37.5 µg
75 µg
150 µg
85 kg
42.5 µg
85 µg
170 µg
95 kg
47.5 µg
95 µg
190 µg
105 kg
52.5 µg
105 µg
210 µg
Titration logic
Titration decision logic (CNS-safety oriented)
Trigger
Action
Rationale
New insomnia, agitation, anxiety, irritability
Hold or reduce
Mood-circuit modulation is a theoretical risk
Headache, dizziness, neurological symptoms
Hold
CNS-active candidate; no human safety range
BP/HR instability
Hold and evaluate
TREK channels are relevant in cardiac physiology
GI cramping / motility change
Reduce / hold
TREK biology has GI smooth-muscle relevance
Mood worsening or suicidal ideation
Hard stop + urgent clinical evaluation
Psychiatric indication is unvalidated
Pregnancy / lactation
Hard stop
No reproductive safety data
Seizure activity or aura change
Hard stop
Excitability-modulating mechanism
Concurrent serotonergic drug changes
Hold
Avoid confounding mood / serotonergic effects
No measurable benefit after 2–4 weeks
Stop / reassess
No validated clinical endpoint
Biomarker scaffold
Biomarker monitoring scaffold (none validated for PE-22-28)
IV use must not be positioned as a wellness/clinic protocol. Grade C/D.
Note · IV
IV is animal-context only
Point
Detail
Source
Related spadin rodent literature
Human IV dose
Not established
Default modeled route
SC (still speculative)
Oral route
Not recommended as a page protocol
Grade D
Dose
Not established.
Rationale
Oral peptide stability and bioavailability are not established for PE-22-28; a 7-residue peptide is vulnerable to GI proteolysis.
Of conceptual interest only. Grade D.
Oral feasibility
Why oral is not modeled
Barrier
Detail
Proteolysis
GI peptidases degrade short peptides
Absorption
Low oral bioavailability expected
Data
No PE-22-28 oral PK exists
L2 · Reconstitution math (research only)
Reconstitution & Dose Calculator
PE-22-28 has no approved clinical dosing. This calculator validates concentration / draw-volume arithmetic only — the same mg→mL math used throughout the atlas — and the outputs are research/hypothesis figures, not treatment doses. It is a CNS-active experimental peptide with no human safety data; anyone considering it for depression or recovery should be under qualified medical care. Verify purity, sterility, and storage; use only product from a licensed research source.
Concentration
—
Draw volume
—
Units (U-100)
—
Aliquots/vial
—
Basis
—
04 · Combinations (theoretical)
Combinations — all theoretical.
No controlled combination studies exist for PE-22-28. The pairings below are mechanistic/thematic only, included to map the research landscape — not protocols. Because PE-22-28 is a CNS-active experimental peptide with no human safety data, every combination carries the overriding caution against unsupervised use, especially with psychiatric medications.
PE-22-28 + SSRI / SNRI
Theoretical · caution
PE-22-28SSRI / SNRIMood circuitry
Both intersect mood circuitry, and spadin-family work overlaps conceptually with antidepressant models. TREK-1 modulation interacts with serotonergic signaling. But this must not be recommended clinically — risk of mood activation, confounding, and serotonergic adverse effects. Any psychiatric-medication change belongs with a prescriber. Grade D/P.
Element
Concern
Grade
Serotonergic overlap
Activation / confounding
D/P
Supervision
Prescriber-only
—
PE-22-28 + Neurorehab (post-stroke)
Preclinical theme
PE-22-28Stroke rehabNeurogenesis
Animal data connect sortilin-derived peptides to stroke recovery and post-stroke depression. Pietri et al. reported protective effects on stroke recovery and post-stroke depression. This is not a basis for self-treatment — acute stroke is a medical emergency requiring immediate professional care; PE-22-28 has no validated human stroke role. Grade C/D.
Element
Status
Grade
Animal recovery signal
Preclinical
C
Acute stroke self-use
Never — emergency care
—
PE-22-28 + Neuroplasticity Lifestyle
Thematic only
PE-22-28Exercise / sleepCognitive rehab
Exercise, sleep, and cognitive rehab support neuroplasticity, and PE-22-28's neurogenesis signal is mechanistically separate. PE-22-28 induced neurogenesis and PSD-95 synaptogenesis in rodents. BDNF and similar markers are not validated for PE-22-28, so this pairing is thematic, not evidence-based. Grade D/P.
Lever
Effect
Grade
Lifestyle neuroplasticity
Independent support
A (general)
PE-22-28 add-on
Mechanistically separate
D/P
PE-22-28 + Metabolic / Beta-Cell Model
Preclinical
PE-22-28Beta-cell survivalCREB
A CREB/beta-cell survival hypothesis comes from preclinical work. Sortilin-derived peptides supported beta-cell survival through CREB signaling under inflammatory stress. This is not a diabetes treatment, and human glucose effects are unknown. Grade P/C.
Finding
Model
Grade
Beta-cell survival
Cell / inflammatory stress
P/C
Human glucose effect
Unknown
—
Hard-constraint clinical note — Avoid PE-22-28 combinations in anyone with active suicidality, a history of bipolar mania/hypomania, uncontrolled seizure disorder, pregnancy/lactation, acute stroke outside emergency care, or unstable cardiovascular disease — because human safety and psychiatric-activation risk are not established. Depression and stroke are serious conditions with proven, supervised treatments; an unapproved research peptide is not a substitute, and any psychiatric-medication interaction must be managed by a prescriber.
05 · Safety & contraindications
Safety is defined by the absence of human data.
There are no direct PE-22-28 human adverse-event data. Its safety picture is therefore mechanism-derived: because TREK-1 biology spans CNS excitability, mood, cardiac, pain, and GI smooth-muscle systems, the theoretical risk set centers on neuropsychiatric activation, seizure/excitability uncertainty, and cardiac/GI effects. As a CNS-active experimental peptide with antidepressant-like activity, the highest-priority cautions are psychiatric (mania, suicidality) and excitability (seizure).
Safety signals & theoretical risks
No human safety datasetDirect PE-22-28 human adverse-event data were not found — the dominant fact. Grade D.
Cardiac / GITREK channels have cardiac and GI smooth-muscle relevance — autonomic/motility uncertainty. Grade P.
ImmunogenicityPeptide immunogenicity / injection reaction risk is not characterized.
Research-reagent statusA research-use-only reagent, not an approved drug — unknown product quality outside controlled sourcing.
Practical safety framework
Highest-priority cautions
Active suicidality, bipolar spectrum (mania/hypomania history), and uncontrolled seizure disorder are the clearest reasons not to use PE-22-28 — its excitability-raising, mood-active mechanism could worsen all three. Depression deserves evidence-based, supervised care.
If studied in a research context
Baseline and ongoing mood scales, sleep logs, BP/HR, neurological symptom checks, and (conservatively) ECG if cardiac risk factors exist. None of these thresholds is validated for PE-22-28 — they are general CNS-active-compound safety overlays.
Stop triggers
Hard-stop on any seizure-like symptom, mood worsening or suicidal ideation, mania/hypomania signs, pregnancy, or allergic/injection reaction. Stop and reassess if there is no measurable benefit after 2–4 weeks — there is no validated endpoint or duration.
Contraindications & cautions
Condition
Concern
Severity
Active suicidality
Unvalidated antidepressant-like agent
High
Bipolar spectrum (mania/hypomania)
Theoretical mood-destabilization / mania risk
High
Seizure disorder
Neuronal-excitability modulation
High
Pregnancy / lactation
No reproductive safety data
High
Pediatric use
No safety / PK data
High
Cardiac arrhythmia / antiarrhythmic use
TREK channels have cardiac relevance
Moderate–High
Unstable cardiovascular disease
Autonomic uncertainty
Moderate–High
GI motility disorder
TREK GI smooth-muscle relevance
Moderate
Unstable psychiatric disease
Mood activation risk
High
Diabetes treatment substitution
Beta-cell findings are preclinical only
High
Acute stroke (self-treatment)
Medical emergency; requires professional care
High
Athlete subject to testing
WADA S0 non-approved substance
High
Concurrent serotonergic-drug changes
Confounding / activation
Monitor
Unverified / non-research-grade product
Purity / sterility / identity unknown
Avoid
06 · Evidence base
What the evidence actually shows.
PE-22-28 has a credible, internally consistent preclinical rationale — a short spadin analog with high TREK-1 potency and rodent/cellular signals across antidepressant-like behavior, hippocampal neurogenesis, post-stroke recovery, and beta-cell survival. What it does not have is human evidence: no interventional trial, no validated PK, no dose-ranging study, no controlled efficacy data, and no long-term safety profile. The verdict is low-to-very-low for clinical use, moderate for target biology.
Human trials
None
No PE-22-28 interventional human trial identified; no approved or validated human dosing. Research-stage.
Preclinical · 2017
0.12 nM
Djillani: PE-22-28 designed from spadin degradation products; IC₅₀ 0.12 nM, neurogenesis in 4 days, ~23 h action. Key paper.
Parent · 2010
Spadin
Mazella/Heurteaux: spadin as a sortilin-derived TREK-1-targeting antidepressant-like peptide. Foundation.
Human biomarker
n≈204
Serum sortilin-derived propeptide studied as a post-stroke-depression marker — biomarker, not PE-22-28 treatment. Observational.
C/PPreclinical · spadin-analog optimization
Djillani et al. 2017 — shortened spadin analogs (the PE-22-28 paper)
The defining paper. From spadin's blood-degradation products, the authors designed PE-22-28; on hTREK-1/HEK patch-clamp it showed IC₅₀ 0.12 nM (vs spadin's 40–60 nM), reduced forced-swim immobility and novelty-suppressed-feeding latency, induced dentate-gyrus neurogenesis after 4 days, raised PSD-95 synaptogenesis, and extended action to ~21–23 h (G/A- and biotin-G/A- analogs) vs spadin's ~7 h.
Mazella et al. 2010 — spadin, a sortilin-derived TREK-1 antidepressant concept
Described spadin as an antidepressant-like sortilin-derived peptide that specifically blocks TREK-1 in rodents — the foundational discovery establishing TREK-1 as a mood-regulation target and the lineage from which PE-22-28 was later derived.
Pietri et al. 2019 — sortilin-derived peptides in stroke recovery
First evidence of protective effects on stroke recovery and post-stroke depression from sortilin-derived peptides in rodent ischemia models — extending the spadin/PE-22-28 story from mood into neuroprotection and recovery.
Reported that sortilin-derived peptides promote pancreatic beta-cell survival through CREB signaling under inflammatory stress — the metabolic branch of the PE/spadin pharmacology, mechanistically distinct from the CNS TREK-1 story and entirely preclinical.
Ma et al. 2020 — spadin antagonizes arachidonic-acid activation of TREK-1
Electrophysiology showing spadin selectively antagonized arachidonic-acid activation of TREK-1, likely through an allosteric / state-dependent mechanism rather than simple pore block — refining how the spadin family engages the channel.
Djillani et al. — fighting depression with TREK-1 blockers
Review of TREK-1 as an antidepressant target, focused on spadin and its short analogs; documents the ~21–23 h action duration of G/A-PE-22-28 / biotin-G/A-PE-22-28 vs spadin's ~7 h and frames the goal of testing these long-lasting peptides in future trials.
Djillani et al. — role of TREK-1 in health & disease (CNS focus)
Reviews TREK-1 across CNS function — mood, pain, ischemia, neuroprotection — establishing both the therapeutic rationale and the breadth of physiology that underlies PE-22-28's theoretical off-target safety considerations.
PPreclinical · TREK-1 selectivity (no seizure/cardiac)
Moha ou Maati et al. 2012 — spadin lacks epileptogenic / cardiac side effects
Showed spadin avoided the epileptogenic and cardiac side effects seen with broader TREK-1 modulators — the selectivity argument that motivated developing potent, specific spadin analogs like PE-22-28 rather than non-selective channel drugs. selectivity evidence.
Sortilin-deficient mice displayed altered TREK-1 function and decreased depression-like behavior — genetic support for the sortilin → spadin → TREK-1 → mood axis that the PE-22-28 program is built on. genetic support.
A human biomarker cohort (not a PE-22-28 treatment study) examining whether serum sortilin-derived propeptide concentrations relate to long-term post-stroke depression — the closest the lineage comes to human data, and it is observational.
Extended the TREK-1 antidepressant model by showing TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex — adding a cortical-circuit dimension to the hippocampal-neurogenesis findings of the spadin-analog work. cortical plasticity.
The reagent-supplier record: PE-22-28 as a potent TREK-1 inhibitor (IC₅₀ ≈ 0.12 nM), water-soluble to ~2 mg/mL, stored at −20 °C, for laboratory research use only — the source confirming its research-reagent (not drug) status.
GRADE summary — Overall evidence strength is low-to-very-low for clinical use and moderate for preclinical target biology. PE-22-28 has a credible mechanism as a potent, selective TREK-1/KCNK2 inhibitor with rodent/cellular evidence for antidepressant-like behavior, rapid hippocampal neurogenesis, post-stroke recovery, and beta-cell survival. The missing pieces are major: no validated human PK, no approved dosing, no dose-ranging or controlled efficacy trial, and no long-term human safety profile. Honest positioning: "a mechanistically elegant, preclinically promising TREK-1 research peptide — not an approved antidepressant, and not ready for human therapeutic use."
07 · Compare & contrast
PE-22-28 vs the TREK-1 / antidepressant-peptide field.
PE-22-28 is the most optimized member of the spadin/sortilin TREK-1 family — more potent and stable than parent spadin, with modified analogs (G/A-, biotin-G/A-) pushing duration further. It sits apart from BDNF-pathway mimetics, which share only the broad neuroplasticity theme and act through entirely different receptors. Correctly classified, it is an ion-channel modulator, not a neurotrophin mimetic.
L1 · Consumer — PE-22-28 is an experimental brain-research peptide related to spadin, a naturally inspired peptide studied for mood and recovery pathways. It is not an approved antidepressant or medical treatment, and the current science is mostly animal- and lab-based. It is sold only as a research reagent, and depression and stroke are serious conditions that deserve proven, supervised care.
L2 · Clinical — PE-22-28 is a shortened sortilin-derived spadin analog investigated as a potent, selective TREK-1/KCNK2 inhibitor with preclinical antidepressant-like, hippocampal-neurogenesis, neurorecovery, and beta-cell-survival signals. Its clinical use is not established because human pharmacokinetics, dosing, efficacy, and safety data are lacking — and its CNS-active mechanism carries theoretical psychiatric, seizure, and cardiac/GI cautions.
L3 · Research — PE-22-28 (GVSWGLR) is the smallest spadin fragment retaining high-affinity TREK-1 inhibition (IC₅₀ 0.12 nM), engineered from spadin blood-degradation products for improved stability (~23 h with G/A- and biotin-G/A- analogs). The proposed cascade: TREK-1 block → reduced K⁺ leak → increased neuronal excitability → serotonergic firing and hippocampal neurogenesis/synaptogenesis → antidepressant-like behavior; a separate CaM-kinase/CREB branch supports beta-cell survival. All translational claims remain preclinical.
08 · References & evidence
Source register.
Evidence grades reflect the strength of support for the specific claim cited, not the prestige of the journal. For PE-22-28, the firmest sources are the Djillani 2017 optimization paper, the spadin foundation work, the TREK-1 mechanism/biology reviews, and the reagent identity record. There are no human interventional sources — which is itself the most important fact about its development stage.