Bacopa monnieri Promotes Neuronal Development by Regulating the Neurotrophin Signaling Pathway

Bacopa monnieri (L.) Wettst. (Family: Scrophulariaceae) is a well-known edible plant used in ethnic and Ayurveda medicine for centuries to improve memory deficit, enhance cognitive function, and treat nervous system disorders. Despite accumulating in vivo evidence for its cognitive benefits, the detailed mechanisms by which its bioactive compounds act on primary neurons remain elusive. In the present study, we dissect the mechanism by which Bacopa monnieri promotes neuronal development by treating primary hippocampal neuronal cultures with its ethanolic extract (BMEE) and integrating insights from in silico network pharmacology. We identified that BMEE at different concentrations promotes neuritogenesis and has a remarkable impact on early neuronal maturation, and axonal and dendritic outgrowth. Also, BMEE regulated synaptic plasticity by increasing the expression of NMDA receptors. Metabolites of BMEE were identified by gas chromatography-mass spectrometry (GC-MS) analysis, from which a network pharmacology model was constructed, in which BMEE metabolites were projected to regulate the neurotrophin signaling pathway. Indeed, the BMEE-mediated neuritogenic effect was abolished by the presence of a TrkA receptor-specific inhibitor, suggesting that the neuritogenic effect of BMEE is TrkA-dependent. Also, molecular docking following MD simulations supported the idea that BMEE metabolites, particularly δ-Tocopherol and O-methyl-, bind with high affinity to the TrkA receptor (NGF-binding domain). This study collectively illuminates the TrkA-mediated pathway through which Bacopa monnieri promotes neuronal development and suggests that bioactive metabolites from BMEE might hold potential as a source for designing therapeutic agents for various cognitive disorders.