Shortened Spadin Analogs Display Better TREK-1 Inhibition, <i>In Vivo</i> Stability and Antidepressant Activity.
PE 22-28 shows promise as a more effective antidepressant analog of spadin, with enhanced duration of action and significant behavioral improvements in mice.
Where it sits
this study against the rest of the pe 22-28 corpusSummary and findings
This study evaluated the peptide PE 22-28 for its effects on TREK-1 inhibition and antidepressant activity. The peptide was tested in various behavioral models of depression in mice, showing a significant reduction in immobility time and latency to eat. The duration of action for PE 22-28 was reported to be up to 23 hours compared to 7 hours for spadin.
Abstract
Depression is a devastating mental disorder that affects 20% of the population worldwide. Despite their proven efficacy, antidepressants present a delayed onset of action and serious adverse effects. Seven years ago, we described spadin (PE 12-28) as a promising endogenous peptide with antidepressant activity. Spadin specifically blocks the TREK-1 channel. Previously, we showed <i>in vivo</i> that, spadin activity disappeared beyond 7 h after administration. In order to improve <i>in vivo</i> spadin stability and bioavailability, we screened spadin analogs and derivatives. From the study of spadin blood degradation products, we designed a 7 amino-acid peptide, PE 22-28. <i>In vitro</i> studies on hTREK-1/HEK cells by using patch-clamp technique, showed that PE 22-28 displayed a better specificity and affinity for TREK-1 channel compared to spadin, IC<sub>50</sub> of 0.12 nM vs. 40-60 nM for spadin. In the same conditions, we also pointed out that different modifications of its N or C-terminal ends maintained or abolished TREK-1 channel activity without affecting PE 22-28 affinity. <i>In vivo</i>, the antidepressant properties of PE 22-28 and its derivatives were demonstrated in behavioral models of depression, such as the forced swimming test. Mice treated with spadin-analogs showed a significant reduction of the immobility time. Moreover, in the novelty suppressed feeding test after a 4-day sub-chronic treatment PE 22-28 reduced significantly the latency to eat the food pellet. PE 22-28 and its analogs were able to induce neurogenesis after only a 4-day treatment with a prominent effect of the G/A-PE 22-28. On mouse cortical neurons, PE 22-28 and its derivatives enhanced synaptogenesis measured by the increase of PSD-95 expression level. Finally, the action duration of PE 22-28 and its analogs was largely improved in comparison with that of spadin, up to 23 h instead of 7 h. Taken together, our results demonstrated that PE 22-28 and its derivatives represent other promising molecules that could be an alternative to spadin in the treatment of depression.