PE-22-28

Also known as: Spadin fragment, TREK-1 inhibitor peptide

Evidence: Preclinical

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Overview

Truncated analog of the natriuretic-peptide-derived peptide spadin that blocks the TREK-1 potassium channel; studied in rodents for rapid antidepressant and neurogenic effects.

PE-22-28 is a shortened analog of spadin, a peptide derived from the sortilin propeptide. It blocks the TREK-1 two-pore potassium channel, which in rodent studies produces rapid antidepressant-like effects with increased hippocampal neurogenesis and synaptogenesis. No human trials exist; memory and 'nootropic' claims are extrapolation from rodent behavioral assays.

Benefits

Antidepressant-like and anxiolytic effects plus hippocampal neurogenesis in rodent models

Dosing reference

Research dose: Vendor/community range 100 to 500 mcg daily; no published human dose.
Range: 100 to 500 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg

Dose response is biphasic in mice: mini-spadin at 0.03 mcg/kg activated TREK-1 and was neuroprotective, while 3 mcg/kg inhibited it and was antidepressant (Pietri 2019). Published mouse doses were 3.0 to 4.0 mcg/kg intraperitoneally or 1.0 mg/kg by gavage (Djillani 2017). Community protocols are subcutaneous or intranasal; no human pharmacokinetic or safety data exist. Interaction with serotonergic antidepressants is unstudied.

Mechanism

PE-22-28 is a shortened analog of spadin, a sortilin propeptide fragment that blocks the TREK-1 two-pore potassium channel (Mazella et al., 2010). Deleting TREK-1 in mice produced a depression-resistant phenotype (Heurteaux et al., 2006), the rationale for blocking it. Shortened spadin analogs including PE-22-28 inhibited TREK-1 more strongly than spadin, were more stable in vivo and had antidepressant-like activity in mice (Djillani et al., 2017). The dose response on TREK-1 was biphasic (Pietri et al., 2019).

Evidence

Preclinical: animal or in vitro data only

TREK-1 deletion in mice produced a depression-resistant phenotype (Heurteaux et al., 2006)
Spadin, the parent peptide, blocked TREK-1 and had antidepressant-like effects in rodents (Mazella et al., 2010)
Shortened spadin analogs including PE-22-28 showed better TREK-1 inhibition, in vivo stability and antidepressant-like activity in mice (Djillani et al., 2017)
Sortilin-derived peptides improved stroke recovery and post-stroke depression in mice, with a biphasic dose response on TREK-1 (Pietri et al., 2019)
Human-trial status: none. No human pharmacokinetic, dose or safety data

References

Side effects

No human safety data; effects unknown beyond animal studies in rodents. As a TREK-1 potassium channel blocker, its effects on cardiac and neural channels in humans are entirely uncharacterized.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: No human data. More stable in vivo than spadin in mice (Djillani et al., 2017); no half-life figure verified in this audit
Bioavailability: Not measured in humans; no bioavailability figure verified in the published sources
Molecular weight: 848 Da
Sequence: 7-amino acid sequence derived from spadin (sortilin propeptide fragment 22-28)