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A Modified Chinese Herbal Decoction (Kai-Xin-San) Promotes NGF-Induced Neuronal Differentiation in PC12 Cells via Up-Regulating Trk A Signaling.

ABSTRACT: Kai-Xin-San (KXS), a Chinese herbal decoction, has been applied to medical care of depression for thousands of years. It is composed of two functional paired-herbs: Ginseng Radix et Rhizoma (GR)-Polygalae Radix (PR) and Acori Tatarinowii Rhizoma (ATR)-Poria (PO). The compatibility of the paired-herbs has been frequently changed to meet the criteria of syndrome differentiation and treatment variation. Currently, a modified KXS (namely KXS₂₀₁₂) was prepared by optimizing the combinations of GR-PR and ATR-PO: the new herbal formula was shown to be very effective in animal studies. However, the cellular mechanism of KXS₂₀₁₂ against depression has not been fully investigated. Here, the study on KXS₂₀₁₂-induced neuronal differentiation in cultured PC12 cells was analyzed. In PC12 cultures, single application of KXS₂₀₁₂ showed no effect on the neuronal differentiation, but which showed robust effects in potentiating nerve growth factor (NGF)-induced neurite outgrowth and neurofilament expression. The potentiating effect of KXS₂₀₁₂ was mediated through NGF receptor, tropomyosin receptor kinase (Trk) A: because the receptor expression and activity was markedly up-regulated in the presence of KXS₂₀₁₂, and the potentiating effect was blocked by k252a, an inhibitor of Trk A. Our current results in cell cultures fully support the therapeutic efficacy of KXS₂₀₁₂ against depression.

SUBMITTER: Yan L

PROVIDER: S-EPMC5744097 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Kai-Xin-San (KXS) is one of the classic famous traditional Chinese medicine prescriptions for amnesia, which has been applied for thousands of years. Modern pharmacological research has found that KXS has significant therapeutic efficacy on nervous system diseases, which is related to its antioxidant activity. However, the antioxidant material basis and quality markers (Q-makers) of KXS have not been studied. Objective: The objective of this study is to explore the Q-makers of antioxidant activity of KXS based on spectrum-effect relationship. Methods: Specifically, the metabolites in KXS extracts were identified by UPLC-Q-Exactive Orbitrap MS/MS. The fingerprint profile of KXS extracts were established by high-performance liquid chromatography (HPLC) and seven common peaks were identified. Meanwhile, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) test was used to evaluate the free radical scavenging ability of KXS. The spectrum-effect relationship between its HPLC fingerprint and DPPH free radical scavenging activity was preliminarily examined by the Pearson correlation analysis, grey relation analysis (GRA), and orthogonal partial least squares discrimination analysis (OPLS-DA). Further, the antioxidant effect of KXS and its Q-makers were validated through human neuroblastoma (SH-SY5Y) cells experiment. Results: The results showed that 103 metabolites were identified from KXS, and the similarity values between HPLC fingerprint of twelve batches of KXS were greater than 0.900. At the same time, the results of Pearson correlation analysis showed that the peaks 8, 1, 14, 17, 18, 24, 16, 21, 15, 13, 6, 5, and 3 from KXS were positively correlated with the scavenging activity values of DPPH. Combined with the results of GRA and OPLS-DA, peaks 1, 3, 5 (Sibiricose A6), 6, 13 (Ginsenoside Rg1), 15, and 24 in the fingerprints were screen out as the potential Q-makers of KXS for antioxidant effect. Besides, the results of CCK-8 assay showed that KXS and its Q-makers remarkably reduced the oxidative damage of SH-SY5Y cells caused by H2O2. However, the antioxidant activity of KXS was decreased significantly after Q-makers were knocked out. Conclusion: In conclusion, the metabolites in KXS were successfully identified by UPLC-Q-Exactive Orbitrap MS/MS, and the Q-makers of KXS for antioxidant effect was analyzed based on the spectrum-effect relationship. These results are beneficial to clarify the antioxidant material basis of KXS and provide the quality control standards for new KXS products development.

Project description:BackgroundAlleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI.MethodsMCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells.ResultsIt was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus.ConclusionJWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

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A Modified Chinese Herbal Decoction (Kai-Xin-San) Promotes NGF-Induced Neuronal Differentiation in PC12 Cells via Up-Regulating Trk A Signaling.

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