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

Acta Pharmacol Sin. 2016 Feb;37(2):166-76. doi: 10.1038/aps.2015.111. Epub 2015 Dec 21.

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 EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / metabolism
  • Antidepressive Agents / therapeutic use*
  • Cells, Cultured
  • Depression / drug therapy*
  • Depression / metabolism
  • Depression / physiopathology
  • Hippocampus / cytology
  • Hippocampus / physiopathology
  • Magnesium / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Saponins / chemistry
  • Saponins / metabolism
  • Saponins / therapeutic use*
  • Steroids / chemistry
  • Steroids / metabolism
  • Steroids / therapeutic use*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology

Substances

  • Antidepressive Agents
  • Receptors, N-Methyl-D-Aspartate
  • Saponins
  • Steroids
  • timosaponin BIII
  • Magnesium