Identifying quality-markers from Shengmai San protects against transgenic mouse model of Alzheimer's disease using chinmedomics approach
Graphical abstract
Introduction
Traditional Chinese medicine (TCM) has been applied in clinical for thousands of years in Asia, with multi-component and multi-target characteristics (Zhang et al., 2016). Elucidation of the efficacy of TCM is important to understand the scientific value of TCM, and promote the innovation and development of TCM (Qiu et al., 2014, Zhang et al., 2014). However, due to complexity of formulation and vagueness of syndrome or disease, it is difficult to understand its efficacy (Wang et al., 2016). Moreover, there is a challenge in selecting appropriate components for the purpose of quality control. Previously, those components at relatively higher concentrations are preferentially selected as the quality markers (Q-markers), rather than those with better efficacy (Liu et al., 2017). Hence, it is necessary to establish an efficacy evaluation and quality control system of TCM in an objective and systematic way.
Chinmedomics, a newer theory and methodology proposed by our team (Wang et al., 2012), is organic integration of serum pharmcochemistry of TCM and “Omics” technology. In brief, using metabolomics technology to clarify the biomarkers of syndrome, take the biomarkers as targets to evaluated the efficacy of TCM formulation, under the condition of effective treatment to identify the active form of constituents in vivo originated from formulation, and further analyzing the correlation between the exogenous constituents in vivo and endogenous biomarkers to discover the constituents which are highly associated with formulation efficacy as the active constituents (Zhang et al., 2015). This strategy has been successfully applied to research on TCM, such as Wen-Xin formulation, AS1350, and Kai-Xin-San (Liu et al., 2016, Cao et al., 2014, Chu et al., 2016; Wang et al., 2017).
Alzheimer's disease (AD) is a neurodegenerative disease which is difficult to recover after onset, characterized by accumulation of Aβ into senile plaques and hyperphosphorylated tau into neurofibrillary tangles (Spires-Jones et al., 2014). APP/PS1 double-transgenic mouse model, with mutations in the genes for amyloid precursor protein (APP) and presenilins 1 (PS1), are preferable for experimental use because of the early appearance of AD-like pathology and cognitive decline (Bonardi et al., 2011). Shengmai-San (SMS), a traditional Chinese herbal formula, is composed of Radix Ginseng, Radix Ophiopogonis, and FructusSchisandrae. It has long been used for the treatment of Qi-Yin deficiency. The chemical components of SMS were identified mainly including ginsenosides, lignans, steroidal saponins and homoisoflavanones (Wu et al., 2011, Yu et al., 2017). It has been reported to have a protective effect on the brain by reducing inflammatory cytokines and nitric oxide formation (Wang et al., 2005a, Wang et al., 2005b). Experiments have showed that it alleviates amyloid beta (Aβ)-induced cytotoxicity of PC-12 cell (Nishida et al., 2007). However, little is known about the effect of SMS on AD transgenic mice model and the bioactive constituents in SMS. Therefore, in this study, we attempted to explore the effects of SMS on APPswe/PS1dE9 mice, and identify the effective components as Q-markers using chinmedomics approach.
Section snippets
Drugs and reagents
SMS is composed of Radix Ginseng, Radix Ophiopogonis, and FructusSchisandrae. These three crude drugs were purchased from the Harbin Tongrentang Drug Store, and authenticated by Professor Xijun Wang of the Department of Pharmacognosy of Heilongjiang University of Chinese Medicine (Harbin, China). The reference standards: schisandrin, schizandrin A and schizandrin B were of HPLC grade (≥98%) were purchased from Sichuan Wikeqi Bio-Technology Co. Ltd. Anti-beta Amyloid 1-42 antibody was obtained
Immunohistochemistry
Sections were first incubated with 3% H2O2 in 0.01 mol/l PBS for 30 min at room temperature to quench endogenous peroxidase activity, heated for 20 min in 10 mM citrate buffer (PH 6.0) for epitope retrieval, and then incubated overnight at 4 °C with rabbit mAb anti-Aβ1-42 (1:1000; Abcam, London, UK). After rinsing, sections were incubated with biotinylated secondary antibody for 30 min at 37 °C, then processed using 3,3′-diaminobenzidine (DAB) and hematoxylin (Peking, China).
SMS improves the cognition impairment of APP/PS1 mice
To determine the effects of SMS on cognition functions of mice, after 8 months of drug administration, APP/PS1 mice and WT mice were evaluated in Morris water maze test. Among them, the navigation tests were performed to assess the spatial learning function of mice. As showed in Fig. 1A, the latency of each group was demonstrated to decrease over time. As expected, compared with WT mice, the latencies of the APP/PS1 mice was significantly increased on each day (F = 0.02, P < 0.05, repeated
Conclusion
In this work, the chinmedomics strategy was applied to assess the efficacy of SMS against APP/PS1 mice, and to discover the potential quality-markers of SMS. The results of correlation analysis between 33 urine marker metabolites of therapeutic effects and 17 serum constituents showed that schisandrin, isoschisandrin, angeloylgomisin Q, gomisin D, angeloylgomisin H, gomisin M2, ginsenoside F1and20(R)-ginsenoside Rg3 were extremely correlated with the effect of SMS on AD. Eight compounds may be
Acknowledgments
This work was supported by grants from the Key Program of Natural Science Foundation of State (grant nos. 81430093, 81373930, 81673586, 81302905, 81503386), National Key Subject of Drug Innovation (grant no. 2015ZX09101043-005, 2015ZX09101043-011), TCM State Administration Subject of Public Welfare of (grant no. 2015468004), University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (UNPYSCT-2015118), Young Talent Lift Engineering Project of China Association
Conflict of interest
The authors declare no competing financial interests.
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