Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

Abstract

We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin-related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 μM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs.

Antidepressive effect of an inward rectifier K+ channel blocker peptide, tertiapin-RQ

“…Tail suspension test. The tail suspension test (TST) was performed in accordance with the method reported previously [15]. The mouse was hung on a hook using adhesive tape placed 2 cm from the extremity of its tail 50 cm above a table.…”

“…Forced swim test. The forced swim test (FST) was performed in accordance with the method reported previously [15]. Briefly, a Mouse was placed into a 2 L glass beaker containing 12 cm of water (25-27˚C).…”

“…Open field test. The open-field test (OFT) was performed in accordance with a previous report [15]. The open-field consisted of a square (90 × 90 cm), in which the floor was divided into 16 equal squares.…”

“…Recent studies have suggested the involvement of K + channels in mental illness. For instance, mutations in a K + channel resulted in a bipolar disorder [ 13 ], and some K + channel modulators successfully showed an antidepressive effect in mice [ 14 , 15 ]. ROMK channel is also expressed in the brain, but its role in the central nervous system remains unknown.…”

N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels

“…Furthermore, dysregulation of cardiac TREK-1 expression has been observed in patients suffering from atrial fibrillation and heart failure [14,15]. Even though the pharmacological [16,17,18,19,20,21,22] and biophysical [23,24,25,26,27,28] characteristics of hTREK-1 channels have been widely studied, relatively little is known about its posttranslational modifications [29].…”