Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis

Abstract

Background and objective: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS.

Methods: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes.

Results: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets.

Conclusions: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS.

Keywords: Acute ischemic stroke; Epimedii; Icariside II; Phosphodiesterase 5 inhibitors; cGMP-PKG signaling pathway.

Fig. 1

The workflow of this study

Fig. 2

The flow diagram of search, screening and study selection of the systematic review

Fig. 3

Intersection targets of ICS II and AIS

Fig. 4

The network diagram of core targets and non-core targets. The nodes, closing to the center and in dark color represent that they play a key role in the whole network

Fig. 5

GO enrichment analysis of ICS II in treating AIS. GO items and Enrichment score are represented by the x-axis and y-axis, respectively

Fig. 6

Top 10 enrichments of KEGG analysis with ICS II in treating AIS

Fig. 7

Targets-pathway network of ICS II in treating AIS. The green nodes represent the target genes and yellow nodes represent related pathways

Fig. 8

Pathway map of ICS II against AIS. The key targets of ICS II in the treatment of AIS were shown as rose red in the cGMP-PKG signal pathway

Fig. 9

Molecular docking diagram of PRKG1 and ICS II

Fig. 10

RMSD of ICS II. The conformation of all systems has reached a steady-state because the RMSD value fluctuates for the original structure of complex within 0.2 nm which indicates the stability of the structures

Fig. 11

RMSF of ICS II. Most of the residues had low fluctuation values in other regions, which indicated that the residues are stable in binding to the protein