Potential Targets and Action Mechanism of Gastrodin in the Treatment of Attention-Deficit/Hyperactivity Disorder: Bioinformatics and Network Pharmacology Analysis.

Objective: Gastrodin is a main medicinal component of traditional Chinese medicine (TCM) Blume (), presenting the potential for the treatment of attention-deficit/hyperactivity disorder (ADHD). However, the underlying targets and action mechanisms of the treatment have not been identified.

Methods: The gastrodin-related microarray dataset GSE85871 was obtained from the GEO database and analyzed by GEO2R to obtain differentially expressed genes (DEGs). Subsequently, the targets of gastrodin were supplemented by the Encyclopedia of Traditional Chinese Medicine (ETCM), PubChem, STITCH, and SwissTargetPrediction databases. ADHD-associated genes were collected from six available disease databases (i.e., TTD, DrugBank, OMIM, PharmGKB, GAD, and KEGG DISEASE). The potential targets of gastrodin during ADHD treatment were obtained by mapping gastrodin-related targets with ADHD genes, and their protein-protein interaction (PPI) relationship was constructed by the STRING database. The GO function and KEGG pathway enrichment analyses were performed using the ClueGO plug-in in the Cytoscape software and DAVID database, respectively. Finally, the binding affinity between gastrodin and important targets was verified by molecular docking.

Results: A total of 460 gastrodin-related DEGs were identified from GSE85871, and 124 known gastrodin targets were supplemented from 4 databases, including ETCM. A total of 440 genes were collected from the above 6 disease databases, and 267 ADHD-relevant genes were obtained after duplicate removal. Through mapping the 584 gastrodin targets to the 267 ADHD genes, 16 potential therapeutic targets were obtained, among which the important ones were DRD2, DRD4, CHRNA3, CYP1A1, TNF, IL6, and KCNJ3. The enrichment analysis results indicated that 16 potential targets were involved in 25 biological processes (e.g., dopamine (DA) transport) and 22 molecular functions (e.g., postsynaptic neurotransmitter receptor activity), which were mainly localized at excitatory synapses. The neuroactive ligand-receptor interaction, cholinergic synapse, and dopaminergic synapse might be the core pathways of gastrodin in ADHD treatment. Through molecular docking, it was preliminarily verified that gastrodin showed good binding activity to seven important targets and formed stable binding conformations.

Conclusions: Gastrodin might exert an anti-ADHD effect by upgrading the dopaminergic system and central cholinergic system, inhibiting the inflammatory response and GIRK channel, and exerting a synergistic effect with other drugs on ADHD. For this reason, gastrodin should be considered a multitarget drug for ADHD treatment.