Shortened Spadin Analogs Display Better TREK-1 Inhibition, In Vivo Stability and Antidepressant Activity

This study investigated shortened spadin analogs as potential next-generation antidepressants, focusing on the inhibition of the TREK-1 potassium channel. The TREK-1 channel was identified as a target for depression following the discovery that TREK-1 knockout mice display a depression-resistant phenotype.

PE-22-28, a 7-amino acid fragment of spadin (originally 17 amino acids), demonstrated superior pharmacological properties compared to the parent peptide. The affinity for the TREK-1 channel was extraordinary, with an IC50 of 0.12 nM compared to 40-60 nM for full-length spadin — an improvement of approximately 500-fold. Furthermore, PE-22-28 exhibited significantly greater in vivo stability.

The in vivo results were equally impressive:

• Hippocampal neurogenesis observed after only 4 days of treatment (vs. weeks with conventional antidepressants)
• Significant antidepressant activity with duration of up to 23 hours after a single dose
• Efficacy demonstrated in the forced swim test and the tail suspension test

A particularly notable aspect is the rapidity of the neurogenic effect. Classical antidepressants such as fluoxetine typically require 2-3 weeks to induce neurogenesis, whereas PE-22-28 achieved this effect in days. The mechanism involves TREK-1 inhibition, which leads to the activation of intracellular signaling pathways that promote neuronal survival and proliferation.

These findings position PE-22-28 as a promising candidate for the development of rapid-acting antidepressants with a mechanism of action distinct from selective serotonin reuptake inhibitors.