Computational Investigation of Flavonoid-Associated Molecular Pathways in Astrogliosis Modulation

Astrogliosis is characterized by an abnormal increase in the number of astrocytes in the brain due to damage, trauma, infection, ischemia, stroke, autoimmune responses, or neurodegenerative disorders. Glial Fibrillary Acidic Protein (GFAP) is a marker for astrocyte development and astrogliosis. Flavonoids have unclear anti-neuroinflammatory effects in astrogliosis. This computational analysis was the first to investigate the potential interaction between flavonoids and the transcription factors involved in GFAP expression. Using AutoDock Vina, 60 flavonoids with known anti-inflammatory properties were docked to 26 proteins involved in GFAP expression. Toxicities of the flavonoids were predicted using the ProtoxII server, and drug-likeness and pharmacokinetic properties were assessed using the DruLiTo and pkCSM software, respectively. BIOVIA Discovery Studio software was used to evaluate the interactions between flavonoids and target proteins. Among the studied flavonoids, biochanin A, bavachin, apigenin, epicatechin, wogonin, kaempferol, hispidulin, genistein, farrerol, diosmetin, and daidzein displayed drug-like properties, no toxicity, favorable pharmacokinetic properties, and better docking scores for Janus Kinase 1 (JAK1), Janus Kinase 2 (JAK2), I Kappa B Kinase (I-κKB), Serine/Threonine Kinase (AKT), and Histone Acetyltransferase (P300). This in silico study revealed that predictive associations between flavonoids and JAK1, JAK2, I-κKB, AKT, and P300 might affect both GFAP expression and the astrogliosis process via the Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway. The interactions between flavonoid(s) and predicted binding partner(s) were confirmed based on previous studies. These predictive associations are extremely valuable for developing nutritional guidelines and for improving flavonoid-based therapeutic strategies for neurological disorders driven by astrogliosis. This research provides insight for further in vitro and in vivo research.