Innovative approaches for a novel antidepressant from traditional Chinese medicine
William Jia
Prof. William Jia, PhD
Senior Scientist and Principle Investigator, Brain Research Centre,
Associate Professor, Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, Canada V6T 2B5
Abstract:
Many chemical ingredients of TCM drugs are poorly absorbed and therefore do not represent the pharmacological mechanisms of the drug. We proposed that one of better approaches to modernize TCM is to study compounds post absorption and metabolism. Compounds found in the blood or target organs after taking TCM drug can be re-synthesized and combined to form a class of novel drugs namely Post Absorption/Metabolism Drugs (PAMDs). Ginseng has been used as a major ingredient in TCM for treatment of depression for many years in China. A more recent randomized, controlled trial of ginseng in postmenopausal women also reported improvements in mood and anxiety. In the present study, we tested anti-depression effect of a semi-synthesized aglycone ginsenoside S111 that represents one of the post metabolism compounds of ginseng in a series of depression models. Transcriptomics of various brain regions were analysed and compared with that of untreated and fluoxetine, a clinical anti-depressant, treated animals. Our results showed that orally given S111 daily for consecutive 10 days significantly antagonized Reserpine induced various locomotor inhibition in mice. In a 21-day chronic stress induced rat depression model, animals with S111 given daily demonstrated substantial improvement in an open-field test as much as fluoxetine. Furthermore, S111 inhibited 5-HT and NE uptake in the brain in acute tests. However, unlike fluoxetine, S111 does not alter concentrations of those neurotransmitters in the brain in the chronic depression model, suggesting its anti-depressant effect may be mediated by a different mechanism. The transcriptomic study further showed two distinctive gene expression profiles between S111 and fluoxetine, indicating that the two drugs may have quite different anti-depression mechanisms. S111 caused much less disturbance in the normal animals than that of fluoxetine and S111 had a better therapeutic efficiency. However, some genes were commonly regulated by both S111 and fluoxetine, suggesting that those genes may represent a group of targets that are critical for anti-depression. Our results are the first to show that a metabolic product of ginseng can be extremely active and perform better therapeutic functions of ginseng. We also demonstrated that approach of system biology can be used to analyze the complicated biological effects of TCM drugs.
