Convergent and Divergent Pathways Decoding Hierarchical Additive Mechanisms in Treating Cerebral Ischemia–Reperfusion Injury

• Published in: CNS neuroscience & therapeutics 2014-03, Vol.20 (3), p.253-263
• Main Authors: Zhang, Ying‐Ying, Li, Hai‐Xia, Chen, Yin‐Ying, Fang, Hong, Yu, Ya‐Nan, Liu, Jun, Jing, Zhi‐Wei, Wang, Zhong, Wang, Yong‐Yan
• Format: Article
• Language: English
• Subjects: Additive effect; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Biological and medical sciences; Cardiology. Vascular system; Cerebral ischemia; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Drug combination; Drug Therapy, Combination; Drugs, Chinese Herbal - therapeutic use; Flavonoids - therapeutic use; Infarction, Middle Cerebral Artery - drug therapy; Ingenuity Pathway Analysis; Injuries of the nervous system and the skull. Diseases due to physical agents; Iridoids - therapeutic use; Ischemia; Male; Medical research; Medical sciences; Mice; Mice, Inbred Strains; Microarray Analysis; Molecular Sequence Data; Neurology; Original; Pharmacological mechanism; Principal Component Analysis; Reperfusion Injury - drug therapy; Signal Transduction - drug effects; Traumas. Diseases due to physical agents; Vascular diseases and vascular malformations of the nervous system
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12205

Summary Introduction Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. Aims We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. Results We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. Conclusions These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.