K̲ai-X̲in-S̲an (KXS), originated from traditional Chinese medicine (TCM), is
a herbal formula that has been used for treating mental disorders, especially
memory loss and depression, in China for thousands of years. KXS has a
combination of four herbs: Ginseng Radix et Rhizoma (GR; root and rhizome
of Panax ginseng C. A. Mey.; Araliaceae family), Polygalae Radix (PR; root of
Polygala tenuifolia Wild.; Polygalaceae family), Acori Tatarinowii Rhizoma (ATR; rhizome of Acorus tatarinowii Schott; Acoraceae family), and Poria (PO;
sclerotium of Poria cocos (Schw.) Wolf; Polyporaceae family). KXS contains
two paired-herbs: GR-PR aiming at activating ”Xin-qi”, i.e., the benefit of brain
functions and enhancing memory; ATR-PO aiming at eliminating dampness
and inducing resuscitation, i.e. functions related to brain function. These two
paired-herbs are contributing to KXS clinical efficiency, and different
compatibilities of paired-herbs are leading to three KXS, i.e. KXS-652 formula
of GR:PR:ATR:PO as 1:1:25:50; KXS-984 of GR:PR:ATR:PO as 1:1:1:2;
DZW-652 of GR:PR:ATR:PO as 3:2:2:3 (the number indicated the year it was created).
In previous study, different compatibilities of GR-PR and ATR-PO showed
diverse actions on neuronal differentiation that is considered as a crucial target
for anti-depression. Thus, there might be an optimal ratio of paired-herbs to
form a new patentable herbal combination showing promising effects on anti-depression. Here, we aimed to prepare an optimized formula by searching
for the compatibility of paired-herbs on neuronal differentiation. Whether the new combination possessed promising effects on anti-depression by other therapeutic targets, e.g. expression of neurotrophic factors and synapse formation would be further tested.
To explore an optimized ratio of paired-herbs in KXS, the chemical and
biological assessments of single herbal extract, paired-herb extracts and KXS extract were determined and compared. Cultured pheochromocytoma (PC12) cells were used to study the effects of herbal extracts on neuronal differentiation, where neurofilaments were used as indicative markers. By
revealing the herbal extract-induced transcriptional activity of neurofilaments,
an optimized ratio (named KXS
2012, the number indicated the year it was created) of paired-herbs was revealed: the significant synergistic effects of KXS
2012 were analyzed by Compusyn, a computer program in examining drug
interaction in multiple drug effect analysis according to median-effect principle.
Several cell models were employed to study the effects of KXS
2012 on three anti-depressive targets: neuronal differentiation, synaptogenesis and neurotrophic factor expression. In neuronal differentiation, KXS
2012 showed
better effect, as compared to KXS, in promoting differentiation of cultured PC12 cells, including the potentiation of nerve growth factor (NGF)-induced neurite outgrowth and neurofilament expression. The potentiating effect of
KXS
2012 might be mediated through NGF receptor, tropomyosin receptor kinase A (Trk A): because the receptor expression was markedly increased in KXS
2012-treated PC12 cells, and the potentiating effect was inhibited by K252a (an inhibitor of tyrosine phosphorylation of Trk A). In synaptogenesis study, KXS
2012 showed better effect on inducing expression of synaptotagmin than
that of KXS. In addition to induce the expression levels of NGF, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), KXS
2012 greatly induced the expression of neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), as compared to KXS. The induction of neurotrophic
factors was inhibited by H89 [Protein kinase A (PKA) inhibitor] and U0126 [Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK1/2) inhibitor], indicating that KXS or KXS
2012-induced neurotrophic factor expression was mediated through cAMP-PKA and MAPK signaling pathways.
At last, depressive animal models were employed to reveal the efficacy and action mechanism of KXS
2012. In ICR mice, KXS
2012 reduced cumulative
immobility time in forced swimming and tail suspension tests. In CMS-induced depressive SD rat model, KXS
2012 reversed depressive behavior and up-regulated the levels of neurotransmitters and neurotrophic factors in
depressive brain. Compared with KXS, KXS
2012 largely restored depressive
behavior; increased the level of dopamine in striatum; up-regulated the expression of NGF, NT4/5, Trk B and Trk C in CMS-induced depressive rats. The results indicated that KXS
2012 might exert robust anti-depressive function by further up-regulating neurotransmitters and neurotrophic factors in
depressive brain.
In conclusion, KXS
2012 exerted anti-depressant function in animals by modulating neurotransmitters, neuronal differentiation, synaptogenesis and neurotrophic factor expression. Thus, KXS
2012 could be developed as a new patentable regimen for anti-depression.
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