A Network Pharmacology–Based Analysis of the Protective Mechanism of Miao Medicine Xuemaitong Capsule Against Secondary Brain Damage in the Ischemic Area Surrounding Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating disease with the high mortality. The poor outcome of ICH is partially due to a combination of various secondary insults, including in the ischemic area. Xuemaitong capsule (XMT), a kind of traditional Chinese medicine, has been applied to clinic practice. The purpose of this study is to explore the mechanism of XMT in alleviating secondary damage in the ischemic area after ICH. We screened XMT target, compound components, and ICH-related targets using network pharmacology, cluster analysis, and enrichment analysis. We found that the tumor necrosis factor (TNF) signaling pathway might be the key signaling pathway for XMT treatment of ICH. An ICH rat model was established, as demonstrated by poor neurologic score. In the ICH rats, Western blot analysis and immunofluorescence indicated the upregulated expression of TNF receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and caspase-3 (CASP3). Importantly, administration of XMT alleviated inflammation, edema, and increased perfusion in the ischemic area, whereas the expression of TNFR1, MAPK, NF-κB, and CASP3 was decreased. Furthermore, Fluoro-Jade B and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining revealed that XMT application also inhibited apoptosis and degradation of ischemic area neurons. In conclusion, this evidence elucidates that XMT alleviates neuron apoptosis, ischemic area inflammation, edema, and perfusion through the TNFR1-mediated CASP3/NF-κB/MAPK axis. SIGNIFICANCE STATEMENT: Tumor necrosis factor (TNF) is the key signaling pathway of Xuemaitong (XMT) to intervention during intracerebral hemorrhage. Fourteen key targets [intercellular adhesion molecule 1, interleukin (IL) 6, TNF, C-C motif chemokine ligand 2, prostaglandin-endoperoxide synthase 2, v-rel reticuloendotheliosis viral oncogene homolog A, matrix metalloproteinase 9, endothelin-1 (EDN1), mitogen-activated protein kinase (MAPK) 1, fos proto-oncogene protein, caspase-3 (CASP3), jun proto-oncogene, IL1B, MAPK8] are retrieved from the data base. XMT can inhibit neuron apoptosis in the ischemic area via regulating TNF receptor 1 (TNFR1)/CASP3. XMT alleviates inflammation and edema through regulating TNFR1/nuclear factor-κB and TNFR1/MAPK signaling pathways. XMT alleviates hypoperfusion in the cerebral ischemic area through mediating TNFR1/MAPK/EDN1.