Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Abstract

Aim: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. Methods: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg -1 ·d -1 ) or a positive-control drug, fluoxetine (10 mg·kg -1 ·d -1 ) for 3 weeks. Behavioral assessments were carried out every week. Results: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC 50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltagedependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. Conclusion: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

Identifying the active components of Baihe–Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests

“…Zhang et al had already demonstrated that timosaponin BIII significantly ameliorated depressive effects in rats by regulating inflammatory cytokines, BNDF signaling and synaptic plasticity [29]. We found that YY-21 and YY-23, two modified derivatives of timosaponin BIII, also exhibited antidepressant activity in the animal model [30, 31]. The validated results regarding the antidepressant activities of timosaponin BII and timosaponin BIII were consistent with previous literature reports.…”

Effect of triethylamine treatment of titanium silicalite-1 on cyclohexanone ammoximation in a continuous system

“…All the samples exhibit These results indicate that the formation of the small amounts of the anatase after TEA treatment does not accelerate the ineffective decomposition of H 2 O 2 , which is in agreement with that reported in Ref. [62]. However, the catalyst lifetimes of these samples are significantly different.…”

Prefrontal AMPA receptors are involved in the effect of methylphenidate on response inhibition in rats

“…Top-down control of the PFC depends on the output neurons within it. Glutamatergic neurotransmissions participate in many brain functions [34] and are key to the output neurons in the PFC; however, it is unknown whether glutamate receptors in the PFC play a role in the effect of MPH on response inhibition.…”