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 in vivo that, spadin activity disappeared beyond 7 h after administration. In order to improve in vivo 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. In vitro 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, IC50 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. In vivo, 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.
Highlights
Depression is one of the most common mood disorders that represents a heavy economic burden in industrialized countries (Smith, 2014)
We identified two shortened peptides. By comparing their ability to inhibit TREK-1 channel expressed in the hTREK-1/HEK cell line (Moha ou Maati et al, 2011), we identified the shortest efficient sequence that only contained 7 amino-acid called PE 22-28
In order to study the effects of shortened spadin analogs on hTREK-2, hTASK-1, hTRAAK and hTRESK, the native HEK293 cells were transfected with DNAs corresponding to the channels using JetPEI (Polyplus-transfection, France) following the provider’s instructions
Summary
Depression is one of the most common mood disorders that represents a heavy economic burden in industrialized countries (Smith, 2014). To reduce the frequency and occurrence of these side effects, these drugs were replaced by a generation of ADs more specific and with lesser adverse effects This includes serotonin-selective re-uptake inhibitors (SSRIs) and norepinephrine selective re-uptake inhibitors (NSRIs) that are widely used nowadays and recommended as first-line treatment for depression (Nestler et al, 2002; Cleare et al, 2015). Multimodal drugs, such as vortioxetine or vilazodone are a new class of ADs latterly approved by the US Food and Drug Administration for the treatment of major depressive disorders (Wang et al, 2015; Sowa-Kucma et al, 2017) These drugs have not represented a clear improvement of antidepressant efficacy, but vortioxetine showed beneficial effects in depression-related cognitive impairment whereas vilazodone appeared to induce minor sexual dysfunctions (Deardorff and Grossberg, 2014; Li et al, 2015; Thase et al, 2016). We have identified the selective two-pore domain potassium channel TREK-1 (TWIK-related potassium channel-1) as a potential target for depression treatment
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