title: Tetramethylpyrazine identified by a network pharmacology approach ameliorates methotrexate-induced oxidative organ injury.
abstract: BACKGROUND
  Tetramethylpyrazine (TMP) is one of the active constituents extracted from a frequently used herb, Ligusticum wallichii Franchat (Chuan-Xiong in Chinese), in traditional Chinese medicine. TMP can exert multiple pharmacological actions such as anti-inflammatory, anti-oxidative damage, anti-platelet and neuroprotective effects, and its applications deserve further explored.
  
  
  OBJECTIVE
  This study aimed to determine the new role of TMP identified by a network pharmacology approach to alleviate the methotrexate (MTX)-induced oxidative injury and characterize their mechanism of combinational actions.
  
  
  METHODS
  A network pharmacology-based screening strategy is applied for target profile prediction and pharmacological characterization of herbal compounds, which is used to guide the following in vitro and in vivo experiments. The effect of herbal compounds identified by network pharmacology approaches to reduce the toxicity of MTX was assessed by MTX-induced rat toxicity model. The potential targets of TMP in this study were evaluated using standard protocols provided by Cerep, Inc.
  
  
  RESULTS
  This strategy identified TMP from Ligusticum wallichii Franchat as a potent compound for ameliorating the oxidative organ injury of MTX. According to the predicted target profiles of TMP, a possible mechanism of the abrogation of MTX-induced toxicity is that TMP could upregulate cAMP by inhibiting phosphodiesterase (PDE) 10A2 activity. Another novel finding is that the competitive binding and antagonistic effects of TMP on adenosine receptor 2A and 2B appear to play important roles in the TMP-mediated reversal of MTX-induced hepatic injury.
  
  
  CONCLUSIONS
  TMP identified by a network pharmacology approach could ameliorate MTX-induced oxidative organ injury. This study provides important evidence for the preclinical evaluation of TMP and MTX as a novel combinatorial remedy.
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing, 100084, China; Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, 300457, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China; Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region, 00852, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing, 100084, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Bai
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: He
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Bian
authors.affiliation: China-Japan Friendship Hospital, Beijing, 100030, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region, 00852, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China; Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong Special Administrative Region, 00852, China. Electronic address: lap64067611@126.com.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST/Department of Automation, Tsinghua University, Beijing, 100084, China. Electronic address: shaoli@mail.tsinghua.edu.cn.
authors.forename: Shao
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000097:blood; D055808:Drug Discovery / Q000379:methods; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal; D005260:Female; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D030004:Ligusticum; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism
chemical_list: D004365:Drugs, Chinese Herbal; D011719:Pyrazines; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D000242:Cyclic AMP; C101574:chuangxiong extract; C017953:tetramethylpyrazine; D008727:Methotrexate
keywords: Combination therapy; Methotrexate; Network pharmacology; Oxidative organ injury; Tetramethylpyrazine