Abstract
Naotaifang extract (NTE) is a clinically effective traditional Chinese medicine compound for cerebral ischemia-reperfusion injury. Although NTE can achieve neuroprotective function through different mechanisms, the pharmacodynamic substances of NTE corresponding to these mechanisms have rarely been reported. Alleviating or inhibiting neuronal apoptosis is an important way to achieve neuroprotection. Accordingly, this study has evaluated the effects of NTE on alleviating neuronal apoptosis after cerebral ischemia-reperfusion injury from two levels of cells and tissues. Meanwhile, the serum pharmacochemistry of NTE was analyzed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with the guidance of Chinmedomics. The results included three aspects: (1) NTE could significantly alleviate neuronal apoptosis caused by in vitro cellular models and in vivo animal models; (2) a total of 21 serum differential metabolites was discovered, including adenosine, inosine, ferulic acid, calycosin, salidroside, 6-gingerol, 2-methoxycinnamaldehyde, and so on; (3) the metabolic pathway regulated by NTE was mainly purine metabolism. From these results, it can be concluded that alleviating neuronal apoptosis by NTE after cerebral ischemia-reperfusion injury is one of the important mechanisms to achieve neuroprotection. The pharmacodynamic substances of NTE for alleviating neuronal apoptosis on the one hand are related to components directly absorbed into blood, such as ferulic acid, calycosin, salidroside, 6-gingerol, and 2-methoxycinnamaldehyde and on the other hand are also closely linked to its indirect regulation of purine metabolism in the body to produce adenosine and inosine. Therefore, our research not only identified the main pharmacodynamic substances of NTE that alleviated neuronal apoptosis but also provided a methodological reference for studying other neuroprotective effects of NTE.
Highlights
Stroke is a disease with cerebral ischemia or hemorrhage as its main clinical symptom, which can be divided into ischemic strokes and hemorrhagic strokes
One hour after the last administration, 10 rats in each group were anesthetized with isoflurane, of which five rats were used for 2,3,5-triphenyltetrazolium chloride (TTC) staining, and the other five rats were used for terminal-deoxynucleotidyl transferase/ (TDT-) mediated nick end labeling (TUNEL) detection
Variable importance in projection (VIP)≥1, Student’s t-test p < 0.05, and fold change (FC) ≥2 or ≤0.5 were used as screening criteria for differential metabolic data. e METLIN database was used to identify potential differential metabolites candidates based on their mass spectrometer (MS) signature and tandem mass spectrometry (MS/MS) spectra, as well as eventual contaminants
Summary
Stroke is a disease with cerebral ischemia or hemorrhage as its main clinical symptom, which can be divided into ischemic strokes (i.e., cerebral infarction) and hemorrhagic strokes (i.e., cerebral hemorrhage). Huang et al reported that NTE could affect the expression of nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and hephaestin in the hippocampus of CIRI rats [8]. He et al discovered that the protective effect of NTE on ischemic brain tissue was to reduce the excessive accumulation of glutamate in synapses of neurons by improving the function of glutamate transporters, which eventually reduced excitotoxicity of glutamate [9]. In the practical application of Chinmedomics to study the pharmacodynamic substances of TCM, the high-throughput and high-sensitivity liquid-mass spectrometry (LC-MS) detection technique is often used as the preferred method to analyze transport constituents in serum samples accurately [13]. To summarize, guided by Chinmedomics, this study used LC-MS to analyze the serum pharmacochemistry of NTE in the hopes of identifying the pharmacodynamic substances of NTE alleviating neuronal apoptosis after CIRI, as well as providing a methodological reference for studying the pharmacodynamic substances of NTE for other neuroprotective effects
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