A Novel Network Pharmacology Strategy Based on the Universal Effectiveness-Common Mechanism of Medical Herbs Uncovers Therapeutic Targets in Traumatic Brain Injury

Abstract

Purpose

Many herbs can promote neurological recovery following traumatic brain injury (TBI). There must lie a shared mechanism behind the common effectiveness. We aimed to explore the key therapeutic targets for TBI based on the common effectiveness of the medicinal plants.

Material and methods

The TBI-effective herbs were retrieved from the literature as imputes of network pharmacology. Then, the active ingredients in at least two herbs were screened out as common components. The hub targets of all active compounds were identified through Cytohubba. Next, AutoDock vina was used to rank the common compound-hub target interactions by molecular docking. A highly scored compound-target pair was selected for in vivo validation.

Results

We enrolled sixteen TBI-effective medicinal herbs and screened out twenty-one common compounds, such as luteolin. Ten hub targets were recognized according to the topology of the protein-protein interaction network of targets, including epidermal growth factor receptor (EGFR). Molecular docking analysis suggested that luteolin could bind strongly to the active pocket of EGFR. Administration of luteolin or the selective EGFR inhibitor AZD3759 to TBI mice promoted the recovery of body weight and neurological function, reduced astrocyte activation and EGFR expression, decreased chondroitin sulfate proteoglycans deposition, and upregulated GAP43 levels in the cortex. The effects were similar to those when treated with the selective EGFR inhibitor.

Conclusion

The common effectiveness-based, common target screening strategy suggests that inhibition of EGFR can be an effective therapy for TBI. This strategy can be applied to discover core targets and therapeutic compounds in other diseases.

Keywords:

• traditional Chinese medicine
• medicinal plants
• luteolin
• AZD3759
• epidermal growth factor receptor
• astrocyte

Abbreviations

Cc, candidate compound; CMC-Na, sodium carboxymethyl cellulose; Ct, candidate target; CCI, cortical impact injury; DMSO, dimethyl sulfoxide; DL, drug-likeness; EGFR, epidermal growth factor receptor; GAP43, growth associated protein 43; GFAP, glial fibrillary acidic protein; H&E, Hematoxylin and Eosin; Mp, medicinal plant; O.B, oral bioavailability; PEG, polyethylene glycol; PPI, Protein-protein interaction; SEM, standard error; TCMSP, Traditional Chinese Medicine Systems Pharmacology; TBI, traumatic brain injury.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 82174259, 81973665], The Science and Technology Innovation Program of Hunan Province/the Hunan Provincial Key Research and Development Program [grant number 2023SK2021, 2022SK2015], the Hunan TCM Scientific Research Program [grant number 2021032, D2022065 and B2024113], The National Science Foundation of Hunan Province (2022JJ40853), and the Postdoctoral Fellowship Program of CPSF (GZC20233202).