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

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.

Dopamine transporter (DAT) knockdown in the nucleus accumbens improves anxiety- and depression-related behaviors in adult mice

“…Although, the FST for mice consists of a single 6-min exposure, some investigators have developed two session procedures as well [60]. In the current study, each mouse was individually forced to swim in a 1-liter glass beaker (Height: 158 mm; Width: 108 mm) containing water at a temperature of approximately 25°C for 6 min as described by others [61][62][63][64]. The mice were unable to escape or rest by touching the bottom of the beaker.…”

Activation of TREK currents by riluzole in three subgroups of cultured mouse nodose ganglion neurons

“…Importantly, ML67-33 strongly activates the three members of the TREK subfamily but not TASK-1, TASK-2, TASK-3 or TRESK [ 23 ]. All these factors and the fact that the outward current activated by riluzole was strongly reduced by spadin, a drug not affecting TASK-1 nor TRESK channels [ 36 , 80 ] indicate that channels of the TREK subfamily should be mediating I Ril .…”

Circadian photoperiod alters TREK-1 channel function and expression in dorsal raphe serotonergic neurons

“…Thus, the lack of significant increase in firing rate in Long photoperiod mice upon TREK-1 inhibition suggests low levels of functional TREK-1 channels in 5-HT neurons. Furthermore, spadin, which we used to inhibit TREK-1, when administrated to mice via intraperitoneal injections elicits an increase in the firing rate of 5-HT neurons in vivo and a decrease in depression-like behaviors 20,23 . Thus, our results provide strong support for programming of TREK-1 channels as a key driver of the behavioral effects of developmental photoperiod.…”