Kai-Xin-San series formulae alleviate depressive-like behaviors on chronic mild stressed mice via regulating neurotrophic factor system on hippocampus.

Kai-xin-san (KXS) is a famous Chinese medicinal formula applied for treating stress-related psychiatric diseases with the symptoms such as depression, forgetfulness and dizziness. In clinic, the composition ratio of KXS is always varied and KXS series formulae are created. Here, we aim to compare the anti-depressive effect of different ratios of KXS and reveal its action mechanism on regulation of neurotrophic factor system. Firstly, daily intra-gastric administration of chemically standardized extracts of KXS series formulae for seven days significantly alleviated the depressive symptoms of chronic unpredictable mild stressed mice displayed by enhanced sucrose consumptions and decreased immobile time of forced swimming coupled with increased locomotor activities. KXS might fulfill this effect by up-regulating the expressions of NGF, BDNF and Trk receptors in hippocampus, which were confirmed by the treatment of corresponding blockers tPA-stop and K252a. The ratio with higher amounts of Ginseng Radix et Rhizoma and Polygalae Radix exerted most profound effect on anti-depression and regulation enzymes in metabolic pathway of neurotrophic factors. These findings suggested that KXS was beneficial for enhancing supplies, up-regulating receptors, and restoring the dysfunction of metabolic pathway of neurotrophic factors, which might account for its anti-depression effect.

Kai-Xin-San, a standardized traditional Chinese medicine formula, up-regulates the expressions of synaptic proteins on hippocampus of chronic mild stress induced depressive rats and primary cultured rat hippocampal neuron.

BACKGROUND: Kai-xin-san (KXS), composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma and Poria, is a famous Chinese medicinal formula applied for treating stress-related psychiatric disease with the symptoms such as depression, forgetfulness and dizziness. Dependent on the symptom differentiation of patients, the composition ratio of KXS was varied and one ratio of 3:2:2:3 was widely applied. However, its molecular mechanism has seldom been investigated. PURPOSE: We aimed to reveal the action mechanism of KXS on anti-depression on synaptic protein regulation in both in vivo and in vitro models. STUDY DESIGN/METHODS: Firstly, the anti-depression effect of KXS was evaluated on a chronic mild stress induced depressive animal model and the mRNA expressions of various synaptic proteins in hippocampus of the depressive rat brains were determined. Then, KXS with different ratios as well as single herb were further evaluated on rat primary cultured hippocampus neurons and the possible signaling pathway was explored. RESULTS: Intra-gastric administration of a chemically standardized KXS for only 6h significantly alleviated the CUMS-induced depressive symptoms displayed by enhanced sucrose consumption and this effect was maintained after daily treatment for seven days. Simultaneously, the mRNA expressions of various synaptic proteins in hippocampus were regulated. Among these synaptic proteins, synaptotagmin (pre-synaptic marker) and post synaptic density protein (post-synaptic marker), with the higher altered magnitude on animal model, were further evaluated on rat primary cultured hippocampus neurons. After neuronal cultures treated with three ratios of KXS at the early and late stages of its life episode, the expression levels of synaptotagmin and PSD95 were both enhanced dramatically via stimulating cAMP dependent pathway. However, different ratio exerted different efficacy. The ratio with higher amounts of Ginseng Radix et Rhizoma and Polygalae Radix showed better effect in early life episode while higher amounts of Acori Tatarinowii Rhizoma and Poria behaved better in late life episode. The contribution of single herb on expressions of synaptic proteins was also evaluated. CONCLUSIONS: KXS was beneficial for synaptogenesis by inducing synaptic protein expressions, which might account for its anti-depression effect.

Kai-Xin-San, a traditional Chinese medicine formula, induces neuronal differentiation of cultured PC12 cells: Modulating neurotransmitter regulation enzymes and potentiating NGF inducing neurite outgrowth.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San, an ancient formula composed of Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma and Poria, was frequently applied for major depression disorders for thousands of years. However, its molecular mechanism has not clearly been investigated. AIM OF THE STUDY: We aimed to reveal the action mechanism of KXS on anti-depression on inducing neuronal differentiation on PC12 cells. MATERIALS AND METHODS: A chemically standardized water extract of KXS was applied onto cultured PC12 cells in determining its effect on neurotransmitter regulation enzymes and neurite outgrowth. RESULTS: Single KXS treatment showed obvious changes in the expression of neurofilament and neurotransmitter regulation enzymes, which in parallel to treatment of nerve growth factor (NGF). Although KXS by itself did not show significant inductive effect on neurite outgrowth of PC12 cells, KXS could potentiate the NGF induced neurite outgrowth. Among the three ratios, K-652 showed the most powerful effect and cAMP-dependent pathway might play the major role. CONCLUSIONS: KXS might exert the anti-depressant-like action of be inducing neuronal differentiation, which supported the clinically usage of this decoction.