Abstract
Gelsemium elegans (Gardner and Champ.) Benth. (Gelsemiaceae) (GEB) is a toxic plant indigenous to Southeast Asia especially China, and has long been used as Chinese folk medicine for the treatment of various types of pain, including neuropathic pain (NPP). Nevertheless, limited data are available on the understanding of the interactions between ingredients-targets-pathways. The present study integrated network pharmacology and experimental evidence to decipher molecular mechanisms of GEB against NPP. The candidate ingredients of GEB were collected from the published literature and online databases. Potentially active targets of GEB were predicted using the SwissTargetPrediction database. NPP-associated targets were retrieved from GeneCards, Therapeutic Target database, and DrugBank. Then the protein-protein interaction network was constructed. The DAVID database was applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis. Molecular docking was employed to validate the interaction between ingredients and targets. Subsequently, a 50 ns molecular dynamics simulation was performed to analyze the conformational stability of the protein-ligand complex. Furthermore, the potential anti-NPP mechanisms of GEB were evaluated in the rat chronic constriction injury model. A total of 47 alkaloids and 52 core targets were successfully identified for GEB in the treatment of NPP. Functional enrichment analysis showed that GEB was mainly involved in phosphorylation reactions and nitric oxide synthesis processes. It also participated in 73 pathways in the pathogenesis of NPP, including the neuroactive ligand-receptor interaction signaling pathway, calcium signaling pathway, and MAPK signaling pathway. Interestingly, 11-Hydroxyrankinidin well matched the active pockets of crucial targets, such as EGFR, JAK1, and AKT1. The 11-hydroxyrankinidin-EGFR complex was stable throughout the entire molecular dynamics simulation. Besides, the expression of EGFR and JAK1 could be regulated by koumine to achieve the anti-NPP action. These findings revealed the complex network relationship of GEB in the “multi-ingredient, multi-target, multi-pathway” mode, and explained the synergistic regulatory effect of each complex ingredient of GEB based on the holistic view of traditional Chinese medicine. The present study would provide a scientific approach and strategy for further studies of GEB in the treatment of NPP in the future.
Highlights
Chronic pain condition is a major health issue that comprises five of the 11 top-ranking conditions lived with disability and is responsible for economic burden worldwide (Vos et al, 2012; Andrew et al, 2014)
We proposed an “ingredient-target-pathway” network to reveal the potential material basis and compatibility molecular mechanisms of GEB against neuropathic pain (NPP) based on the network pharmacology and experimental evidence
A total of 98 compounds in GEB were retrieved from published literature and online databases, and 57 potentially active ingredients were filtered by oral bioavailability (OB) and DL provided by SwissADME (Table 1). 679 potential targets were eventually predicted based on the SwissTargetPrediction after eliminating duplicate targets (Supplementary Table S1). 1,047 targets related to NPP were obtained through the Gene Cards database
Summary
Chronic pain condition is a major health issue that comprises five of the 11 top-ranking conditions lived with disability and is responsible for economic burden worldwide (Vos et al, 2012; Andrew et al, 2014). The prevalence of neuropathic pain (NPP) as a feature of chronic pain was estimated to range from 1 to 17.9% (van Hecke et al, 2014). The current pharmacological interventions in NPP primarily consist of antidepressants or antiepileptics as the first-line treatments (Lunn et al, 2014; Moore and Gaines, 2019), lidocaine plasters, capsaicin high concentration patches, and tramadol as the second-line treatments (van Nooten et al, 2017; Kim et al, 2018), and strong opioids and botulinum toxin A as the thirdline treatments (Sommer et al, 2020). Patients with NPP conventional have an inadequate response with only 40–60% of patients achieving partial relief to the current pharmacological therapy and suffering from side effects include sedation, anticholinergic effects, nausea, and orthostatic hypotension (Dworkin et al, 2007; Cavalli et al, 2019).
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