PE-22-28 is a synthetic, 7-amino-acid peptide derived from spadin, which itself comes from a natural protein called sortilin. It was designed by researchers to be a shorter, more potent version of spadin. Its primary mechanism is blocking the TREK-1 potassium channel in the brain. It is a research compound only — not approved for human use.[4][6]

How does PE-22-28 work?

PE-22-28 blocks a potassium channel in the brain called TREK-1. When TREK-1 is overactive, it's linked to depressive-like states in animal models. By blocking this channel, PE-22-28 helps restore normal neuron activity. Lab studies show it blocks TREK-1 at an IC50 of just 0.12 nM — far more potent than original spadin (40–60 nM) — and its effects last up to 23 hours.[4]

What is PE-22-28 used for in research?

Researchers are studying PE-22-28 primarily for rapid-acting antidepressant effects, neurogenesis (new brain cell growth), synaptogenesis (new neural connections), and recovery from stroke-related brain injury and post-stroke depression. Animal studies showed behavioral improvement in as little as 4 days — far faster than conventional antidepressants in equivalent models.[3][4][1]

How is PE-22-28 dosed in research?

Doses vary widely by research goal. Animal studies have used as little as 0.03 mcg/kg for acute neuroprotection after stroke, up to 3 mcg/kg for antidepressant effects in post-stroke models, and 0.12 mcg per trial in short antidepressant/neurogenesis protocols. See the dosage chart on this page for the full breakdown. These are animal research figures only.[1][4]

How do you reconstitute PE-22-28?

PE-22-28 powder is typically dissolved in sterile bacteriostatic water or saline. Add solvent slowly, swirl gently — don't shake. Because it's active at very low concentrations, careful serial dilution is needed. Store the reconstituted solution refrigerated (2–8°C) for short-term use, or freeze aliquots at −20°C. Avoid repeated freeze-thaw cycles to preserve the peptide's structure and activity.

PE-22-28 has not been tested in human clinical trials. In animal studies, closely related spadin analogs did not produce observable side effects related to pain, seizures, or heart function.[5] Research also suggested no adverse effects on fat cell (adipocyte) physiology.[2] However, the full safety profile in humans is completely unknown. PE-22-28 is strictly a research compound and should never be used for self-administration.

PE-22-28 Dosage Chart — Doses, Protocols & Calculator (Cited)

A synthetic spadin analog and TREK-1 potassium-channel blocker investigated for rapid-acting antidepressant effects.

Goal	Dose	Frequency	Duration	Evidence	Source
Neuroprotection post-stroke (TREK-1 activation, acute phase)	0.03 mcg	1x/day	7 days post-ischemia	Preclinical	PMID 31325429
Post-stroke depression / antidepressant effect (TREK-1 inhibition, chronic phase)	3 mcg	4x/week	per trial	Preclinical	PMID 31325429
Antidepressant effect / neurogenesis (forced swim test, novelty suppressed feeding)	0.12 mcg	per trial	4 days (sub-chronic)	Preclinical	PMID 28955242

BAC water	Concentration	Volume / dose	Units (U-100)
1 mL	5 mg/mL	0 mL	0
2 mL	2.5 mg/mL	0 mL	0
3 mL	1.67 mg/mL	0 mL	0

What is PE-22-28?

PE-22-28 is a tiny synthetic peptide — just seven amino acids long — designed in the lab as a shorter, more potent version of a natural molecule called spadin.^[4] Spadin itself comes from a much larger protein called sortilin, which the body naturally processes and trims into smaller pieces.^[6] One of those pieces, spadin (also written PE 12-28), was discovered to have antidepressant properties. Researchers then went further, studying the breakdown products of spadin in the blood, and identified PE-22-28 as an even more powerful fragment.^[4]

PE-22-28 is classified as a research compound. It has never been approved for human use by any regulatory body. Everything described here comes from preclinical laboratory and animal studies.

How PE-22-28 Works

Think of a neuron (brain cell) like a tiny rechargeable battery. To fire a signal, it needs to manage the flow of charged particles — including potassium ions — in and out through special doors called ion channels. One of these doors is called the TREK-1 potassium channel.

When TREK-1 is too open (too active), it acts like a leak in the battery — the neuron becomes harder to excite, which researchers link to depressive-like states.^[3] PE-22-28 works by blocking TREK-1, essentially closing that leaky door so the neuron can fire more normally.^[4]

What makes PE-22-28 especially interesting is its potency. Lab studies on human TREK-1 cells showed it blocks the channel at an IC50 (the concentration needed to block half the channels) of just 0.12 nM — compared to 40–60 nM for original spadin. In plain terms, it takes a far smaller amount to do the same job.^[4] It also stays active in the body for up to 23 hours, versus only about 7 hours for spadin — a big improvement for research purposes.^[4]

What the Research Shows

Antidepressant Effects in Animal Models

In preclinical behavioral tests — specifically the Forced Swim Test (FST) and Novelty Suppressed Feeding (NSF) test, which are standard ways researchers measure depressive-like behavior in mice — PE-22-28 showed significant effects after just 4 days of sub-chronic treatment.^[4] That speed is notable: classical antidepressants like fluoxetine (Prozac) typically take 3–4 weeks to show effects in equivalent models.^[3]

Neurogenesis and Synaptogenesis

Beyond mood-like behavior, PE-22-28 was found to stimulate neurogenesis — the growth of new brain cells — after just a 4-day treatment window.^[4] It also boosted synaptogenesis (the formation of new connections between neurons), measured by increases in a protein called PSD-95 in mouse cortical neurons.^[4] This mirrors what was seen with original spadin analogs, where neurogenesis and synaptogenesis were linked to lasting antidepressant-like effects.^[3]

Stroke Recovery and Post-Stroke Depression

A 2019 study investigated mini-spadin (a closely related shortened analog) in a mouse model of focal ischemia (a type of stroke) and the depression that can follow it.^[1] Researchers used a clever two-phase dosing strategy: a very low dose early after the stroke to activate TREK-1 and protect brain tissue, then a higher dose later to block TREK-1 and treat depressive-like symptoms.^[1] The compound prevented weight loss, reduced dopaminergic cell loss in a brain region called the substantia nigra, and improved both motor and cognitive deficits caused by the stroke. It also prevented post-stroke depression as measured in the FST and NSF tests.^[1]

The Sortilin Connection

To understand why PE-22-28 matters, it helps to know its origin story. Sortilin — the parent protein — physically interacts with TREK-1 channels at the surface of neurons.^[6] Levels of sortilin-derived peptides in human blood have been found to differ in patients with major depressive disorder, suggesting this whole pathway may be relevant to real-world depression biology.^[6] Earlier work on retro-inverso analogs of spadin (chemically mirrored versions that are harder for the body to break down) also confirmed the TREK-1 blocking approach can boost hippocampal neurogenesis in 4-day treatment windows without triggering side effects on pain, seizure, or cardiac function in animal tests.^[5]

What PE-22-28 Is Being Studied For

Rapid-acting antidepressant effects — blocking TREK-1 to improve depressive-like behavior in animal models^[4]
Neurogenesis — stimulating new brain cell growth^[4]
Post-stroke depression — addressing mood disorders that follow brain ischemia^[1]
Neuroprotection after stroke — low-dose TREK-1 activation in the acute phase^[1]
Synaptogenesis — promoting new neuron-to-neuron connections^[4]

How PE-22-28 Is Dosed in Research

Dosing in animal studies has varied considerably depending on the research goal. The dosage chart on this page summarizes the three main dose ranges documented in published studies — covering neuroprotection after stroke, post-stroke depression treatment, and sub-chronic antidepressant/neurogenesis protocols.^[1][4] Because PE-22-28 is active at very low nanogram-range doses, precise measurement is critical. Use the calculator on this page to help convert research doses accurately. These figures are for reference purposes only and relate strictly to animal research models.

Mixing and Storing PE-22-28

PE-22-28 typically arrives as a lyophilized powder (freeze-dried). To reconstitute it, researchers generally use sterile bacteriostatic water or a saline solution, adding the solvent slowly along the side of the vial and gently swirling — never shaking — to avoid damaging the peptide. Because PE-22-28 is active at extremely low concentrations, serial dilution using a calibrated pipette is recommended to reach the nanogram range needed for research dosing. Once reconstituted, the solution should be stored at 2–8°C (refrigerated) and used within a short window — typically a few days to a week — or divided into single-use aliquots and stored frozen at −20°C to preserve stability. Avoid repeated freeze-thaw cycles, which can degrade peptide integrity. Always work under sterile conditions and label vials clearly with the date of reconstitution.

Sources

First evidence of protective effects on stroke recovery and post-stroke depression induced by sortilin-derived peptides. — Neuropharmacology, 2019. PMID 31325429.
Sortilin derived propeptide regulation during adipocyte differentiation and inflammation. — Biochemical and biophysical research communications, 2017. PMID 27816451.
Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin. — Pharmacology & therapeutics, 2019. PMID 30291907.
Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity. — Frontiers in pharmacology, 2017. PMID 28955242.
Retroinverso analogs of spadin display increased antidepressant effects. — Psychopharmacology, 2015. PMID 25080852.
The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1. — Frontiers in pharmacology, 2018. PMID 30670975.

Storage & handling

Lyophilized (freeze-dried) peptide is typically kept refrigerated and protected from light; once reconstituted with bacteriostatic water it is generally refrigerated at 2–8 °C and used within a few weeks. Follow aseptic technique to avoid contamination, per CDC injection-safety guidance.

Injection technique

Subcutaneous injections are usually given into the fat of the abdomen or thigh: clean the site with an alcohol swab, pinch the skin, insert at the recommended angle, and rotate sites to protect the tissue. See MedlinePlus for a step-by-step subcutaneous-injection guide.

General aseptic-technique and injection references for educational use — they are not specific to any research compound.

PE-22-28 Guide & Dosage Chart