Abstract
Background Amino acids (AAs) in cerebrospinal fluid (CSF) play a pivotal role in cerebral ischemia (CI). BuChang NaoXinTong Capsules (BNC) are widely prescribed in Chinese medicine for the treatment of cerebrovascular and cardiovascular diseases. Methods In order to investigate the therapeutic effects and pharmacological mechanisms of BNC on reversing CI from a system level, an amino acid-protein interaction imbalanced network of CI containing metabolites of AAs, key regulatory enzymes, and proteins was constructed for the first time. Furthermore, a novel method for detecting the ten AAs in CSF was developed by UPLC-QQQ-MS in an effort to validate the imbalanced networks and the therapeutic effects of BNC via analysis of metabolites. Results Based on a middle cerebral artery occlusion (MCAO) rat model, the dynamic levels of amino acids in CSF 3, 6, 12, and 24 h after MCAO were analyzed. Up to 24 h, the accumulated nine AA biomarkers were found to significantly change in the MCAO group compared to the sham group and exhibited an obvious tendency for returning to baseline values after BNC treatment. In addition, based on the imbalanced network of CI, four key enzymes that regulate the generation of BNC-mediated AA biomarkers were selected and validated using an enzyme-linked immunosorbent assay and western blotting. Finally, aromatic-L-amino-acid decarboxylase (AADC) was found to be one of the putative targets for BNC-mediated protection against CI. Conclusion This study provides new strategies to explore the mechanism of cerebral ischemia and help discover the potential mechanism of BNC.
Highlights
Stroke is the third leading cause of death after cardiac ischemia and cancer, often resulting in devastating and crippling health conditions
As for glutamate, the level of glutamate in the BuChang NaoXinTong Capsules (BNC)-treated24h group did not obviously change compared to the MCAO24h group, the level of glutamate in the BNC-treated6h and BNC-treated12h groups proved to be normal compared to that in the corresponding middle cerebral artery occlusion (MCAO) groups (p < 0 01). These findings suggest that the therapeutic effects of BNC on cerebral ischemia were partly due to interferences with the Amino acids (AAs) metabolism of the imbalanced network
An imbalanced network, containing metabolites of AAs, key regulatory enzymes, and proteins associated with cerebral ischemia (CI), was constructed offering the possibility to further understand the pharmacological mechanisms of BNC acting on CI
Summary
Amino acids (AAs) in cerebrospinal fluid (CSF) play a pivotal role in cerebral ischemia (CI). In order to investigate the therapeutic effects and pharmacological mechanisms of BNC on reversing CI from a system level, an amino acid-protein interaction imbalanced network of CI containing metabolites of AAs, key regulatory enzymes, and proteins was constructed for the first time. A novel method for detecting the ten AAs in CSF was developed by UPLC-QQQ-MS in an effort to validate the imbalanced networks and the therapeutic effects of BNC via analysis of metabolites. Based on the imbalanced network of CI, four key enzymes that regulate the generation of BNC-mediated AA biomarkers were selected and validated using an enzyme-linked immunosorbent assay and western blotting.
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