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.
Highlights
Anxiety and depression are common mental disorders, for which most patients are treated with medication
We found no effect on the TREK-1 current (Fig 1B and 1D), excluding the possibility that the activation was caused by the mechanical stretch
The co-administration of amlodipine significantly decreased the time spent in the open arm (p < 0.01, vs ostruthin). These results suggest the involvement of TREK-1 channels in the anxiolytic effect of ostruthin
Summary
Anxiety and depression are common mental disorders, for which most patients are treated with medication. Anxiolytic medicines can lead to tolerance and dependence [1]. Approximately one-third of patients with depression are resistant to current antidepressants, such as serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors [2]. New medicines, for which the mechanism of action is different from current ones, are desired for the treatment of these mental disorders.
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