Vertical and Horizontal Convergences of Targeting Pathways in Combination Therapy with Baicalin and Jasminoidin for Cerebral Ischemia.

Abstract

Baicalin (BA) and jasminoidin (JA) exert an additive effect in the treatment of cerebral ischemia, but the underlying molecular mechanism is still unclear. One hundred mice with focal cerebral ischemia/re-perfusion injury were divided into 5 groups: BA, JA, combination therapy (BJ), sham and vehicle. The differentially expressed genes identified by microarray consisting of 374 cDNAs were uploaded into GeneGo MetaCore software for pathway analyses. Networks were constructed to visualize the interactions of the differentially expressed genes. Among the top ten pathways and processes, we found 5, 3, 2 overlapping pathways and 6, 4, 6 overlapping processes between the BA and JA, BA and BJ, JA and BJ groups, respectively; of which 1 pathway and 3 processes were shared by all the three groups. Six representative pathways and 3 processes were activated only in BJ, such as Gamma-secretase proteolytic targets,etc. These BJ representative targeting pathways showed both vertical (e.g. Cytoplasmic/mitochondrial transport of proapoptotic Bid Bmf and Bim) and horizontal (e.g. Endothelin-1/EDNRA signaling) convergences with those of the BA and JA groups based on the upstream and downstream relationship of cerebral ischemia network, which may help to reveal their additive mechanism in the treatment of cerebral ischemia. Network comparison identified important transcription factors that regulated some of the other BJ related genes, such as cMyb and NF-AT. Such a systemic approach based on multiple pathways and networks may provide a robust path to understand the complex pharmacological variations of combination therapies.