Systems pharmacology reveals the mechanism underlying gastrodiae rhizoma in improving stress-induced cognitive impairment: Protecting hippocampal synapses from excessive microglia-mediated pruning

Ethnopharmacological relevance Gastrodiae Rhizoma (GR), the dried tuber of the orchidaceous plant Gastrodia elata Bl. , has been utilized in traditional medicine for over two millennia. As a valuable traditional Chinese herb in both medical and dietary applications, GR is known for its neuroprotective effects and use in improving cognitive function. Aim of the study To identify the active components of GR that reach the brain and elucidate the mechanisms underlying the alleviation of cognitive impairment. Materials and methods The active compounds of GR decoction that reach the brain were identified using UPLC-Q-TOF-MS/MS. The mechanism by which GR improves cognitive impairment was explored using network pharmacology and molecular docking, and was further verified in mouse models and cell models using immunofluorescence, ELISA, and Golgi staining. Results A total of 54 active compounds in GR that target the hippocampus of mice were identified. Five core components, fourteen key targets, and sixteen signaling pathways contribute to GR's therapeutic effects on cognitive impairment. The above results indicate protecting synapses from excessive microglia-mediated pruning and preserving hippocampal synaptic plasticity, thereby reversing stress-induced deficits in spatial memory, object recognition memory, and social memory. We further confirmed in vitro that gastrodin and parishins in GR suppressed the hyper-activation of microglia by activating the AKT1/NF-κB signaling pathway. Conclusion These results suggest that GR-mediated improvement of stress-induced cognitive impairment may be attributed to its active ingredients, gastrodin and parishins, modulating the AKT1/NF-κB signaling pathway to protect hippocampal synapses from excessive microglia-mediated pruning.