Six-compound combo remedy ameliorates corticosterone-induced depressive behaviors in mice via targeting 5-hydroxytryptamine receptor 1A signaling

Dysregulation of brain innate immunity involving microglia is implicated in the pathology of neurological disorders including depression. Depression is a prominent medical challenge to global public health systems. Synthetic antidepressant drugs are limited by severe side-effects. The present study aimed to identify the active compounds from the well-documented herbal medicine formula Banxia-Houpo decoction (BHD) and discover the underlying mechanisms for tuning microglia. We initially employed LC-MS profiling and network pharmacology analysis to predict the active compound-target interaction networks. We subsequently validated the potential active compounds and targets in a mouse model of corticosterone (CORT)-induced depression and post-synaptic microglia BV2 cells. As results, 64 compounds were identified in the ethanolic BHD extract and predicted to target 25 depression-related genes. Interestingly, the serotonergic synapse pathway received the highest enrichment score while 5-hydroxytryptamine receptor 1A (HTR1A) was targeted by six compounds (i.e., baicalein, luteolin, N-nornuciferine, roemerine, scutellarin, 6-shogaol). In parallel assays, a six-compound combo (SCC) and BHD markedly ameliorated the depressive-like behaviors in CORT-lesioned mice and well protected highly differentiated (HD) PC12 cells against CORT challenge. Moreover, SCC and BHD effectively induced HTR1A expression in mice and post-synaptic microglia BV2 cells. HTR1A antagonist WAY-100635 at 1mg/kg/d via intraperitoneal injection attenuated the effects of SCC and BHD on the depressive behaviors in mice. These results suggest that SCC might be a potential remedy against depression and other neurological disorders via targeting HTR1A in microglia.