A research team led by Prof. Sonata YAU, Member of the Research Centre for Chinese Medicine Innovation (RCMI) and the Mental Health Research Centre (MHRC), and Associate Professor in the Department of Rehabilitation Sciences, has uncovered the significant antidepressant effects of two active ingredients extracted from traditional Chinese medicine (TCM) formula "Yueju Pill". Yueju, an herbal medicine, has demonstrated rapid antidepressant effects, primarily attributed to its iridoid constituents geniposide (GP) and shanzhiside methyl ester (SM).
Prof. Yau’s study investigates the sustained antidepressant efficacy of chronic co-treatment with GP and SM (GS) and elucidates the underlying molecular mechanisms, with a focus on hippocampal neurogenesis and pituitary adenylate cyclase-activating polypeptide (PACAP) signalling.
Using a four-week chronic unpredictable stress (CUS) mouse model, the effects of chronic co-treatment with GS on depression-like behaviours were examined. Adult male C57/BL6J mice received either a vehicle or GS at a high dose, known to induce rapid antidepressant effects, or a lower dose during the final two weeks of CUS. Chronic GS administration significantly alleviated depression-like behaviours, as evidenced by reduced immobility time in the tail suspension test, increased sucrose preference in the sucrose preference test, and reduced latency in the novelty-suppressed feeding test.
Notably, only high-dose GS enhanced hippocampal neurogenesis, indicated by increased number of Ki67-and DCX-positive cells, and upregulated protein expression of PACAP and mTOR signalling, as well as synaptic proteins such as PSD95 in the hippocampus. Importantly, the antidepressant effects of high-dose GS were abolished when PACAP was knocked down in the dentate gyrus. These findings demonstrate that the sustained antidepressant effects of high-dose GS depend on persistent activation of PACAP signalling within the dentate gyrus and are closely linked to enhanced hippocampal synaptic plasticity.
These results suggest that GS offers a promising therapeutic strategy for the long-term treatment of depression, acting through a mechanistic pathway distinct from conventional neurogenesis-dependent interventions. These results have been published in the latest issue of the European Journal of Pharmacology.
Read the full research paper: https://www.sciencedirect.com/science/article/abs/pii/S0014299926001950
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