K2P channels and NMDA receptor as new targets of fast onset antidepressants

Abstract

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD, especially those who are refractory to the traditional antidepressants. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 minutes as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and K2P(TREK1) channels emerged as new drug targets for faster acting antidepressants.