In Plain English:
PE-22-28 (also called Mini-Spadin) is a synthetic heptapeptide derived from positions 22–28 of the sortilin propeptide. It is a highly potent inhibitor of the TREK-1 two-pore potassium channel (IC50 0.12 nM), the same target as its parent peptide Spadin but at 300–500 times lower dose. In rodent models it reversed depressive behaviour within 4 days, stimulated hippocampal neurogenesis, enhanced synaptogenesis (PSD-95 upregulation), and raised BDNF — without the side-effect profile of SSRIs. No human clinical trials have been completed as of 2026.
Research Maturity
Preclinical Only (~3 direct PubMed results for PE-22-28; ~30+ across the spadin/TREK-1 lineage+ Studies)
Focus
Cognition
Mood & Affect
Neuroprotection
Route
Central (preclinical)
IP
IV
Origin
Designed by Djillani et al. (CNRS, Université Côte d'Azur, France, 2017) through systematic truncation of Spadin, itself a 17-AA fragment released by furin cleavage of the neurotensin receptor-3/Sortilin precursor (NTR3). The 7-AA active core (positions 22–28 of the propeptide, sequence GVSWGLR) was identified from in vivo spadin blood-degradation products and shown to retain full TREK-1 specificity. Parent compound Spadin required ~100 µg/kg IP; PE-22-28 is effective at 3–4 µg/kg.
Mechanism
Selective antagonist of TREK-1 (K2P2.1), a two-pore-domain background potassium channel concentrated in the dorsal raphe nucleus, hippocampus, and prefrontal cortex. TREK-1 blockade increases serotonergic neuron firing by preventing potassium-mediated hyperpolarisation, raises extracellular serotonin, and activates cAMP/CREB signalling cascades. Secondary effects include upregulation of BDNF in hippocampus (within 4 days), increased hippocampal neurogenesis (BrdU+ cells nearly doubled vs saline in mouse models), and enhanced synaptogenesis measured by PSD-95 expression in cortical neurons. Highly selective — no cross-reactivity with TREK-2, TRAAK, TASK-1, TASK-3, or TRESK at tested concentrations.
Outcome
Primary rodent study (Djillani et al., Front Pharmacol, 2017, PMID 28955242): PE-22-28 at 3–4 µg/kg IP significantly reduced forced-swim immobility and decreased latency-to-feed in novelty-suppressed feeding after 4-day sub-chronic treatment. BrdU+ hippocampal cells: 1,736 ± 126 (PE-22-28) vs 899 ± 109 (saline control). PSD-95 expression doubled by 36 hours. Effect duration: up to 23 hours vs 7 hours for Spadin. Retroinverso spadin analog study (Veyssiere et al., Psychopharmacology, 2015, PMID 25080852) confirmed 4-day neurogenesis induction with no adverse effects on pain, seizure threshold, or cardiac function across multiple spadin-family analogs. 2019 review (Djillani et al., Front Pharmacol, PMID 31031627) confirmed PE-22-28 superiority across TREK-1 binding metrics. All endpoints are preclinical; zero completed human trials.
