RESUMO
Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood-brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients' death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.
RESUMO
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.