PE-22-28

What is PE-22-28?#

PE-22-28 is a synthetic heptapeptide (Gly-Val-Ser-Trp-Gly-Leu-Arg) developed as an optimized analog of spadin, a naturally occurring peptide derived from the propeptide of sortilin (also known as neurotensin receptor 3). The name "PE-22-28" refers to positions 22-28 of the parent propeptide sequence.

Spadin was originally discovered in 2010 by Mazella and colleagues as a natural TREK-1 potassium channel blocker with antidepressant properties. PE-22-28 was subsequently developed in 2017 by Djillani et al. as a shortened analog with dramatically improved potency, stability, and duration of action.

Mechanism of Action#

PE-22-28 selectively blocks TREK-1 (TWIK-related potassium channel 1), a two-pore domain potassium channel expressed in the brain. TREK-1 knockout mice display a depression-resistant phenotype, establishing this channel as a validated target for antidepressant drug development.

By blocking TREK-1 channels, PE-22-28:

• Increases neuronal excitability in hippocampal and cortical neurons
• Enhances serotonergic neurotransmission
• Induces hippocampal neurogenesis after only 4 days of treatment
• Promotes synaptogenesis as measured by increased PSD-95 expression
• Phosphorylates CREB, a key transcription factor in neuroplasticity

Research Overview#

PE-22-28 has been characterized in a single primary publication (Djillani et al., 2017) demonstrating antidepressant-like activity in the forced swimming test and novelty suppressed feeding test in mice. The compound showed approximately 300-500 times greater potency at TREK-1 compared to spadin, with an IC50 of 0.12 nM, and extended in vivo duration of action from 7 to 23 hours.

Important Considerations#

PE-22-28 is an early-stage preclinical compound with data from a single research group. No human studies have been conducted, and the safety profile is unknown beyond basic tolerability in mouse models. TREK-1 channels have roles beyond mood regulation, including pain sensation and neuroprotection against ischemia, raising potential concerns about off-target effects of chronic TREK-1 blockade.

Key Research Findings#

Shortened spadin analogs display better TREK-1 inhibition, in vivo stability and antidepressant activity, published in Frontiers in Pharmacology (Djillani A et al., 2017; PMID: 28955242):

• The study showed duration of action extended to 23 hours

Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design, published in PLoS Biology (Mazella J et al., 2010; PMID: 20405001):

• The study demonstrated IV treatment produced strong antidepressant effects in mice of 4- day

Related Reading#

• PE-22-28 research studies and evidence
• PE-22-28 dosing protocols
• PE-22-28 side effects profile
• Semax research guide
• Selank research guide