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 Liquid chromatography–mass spectrometry (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 postsynaptic microglia BV2 cells. As a result, 64 compounds were identified in the ethanolic Banxia-Houpo decoction 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 6 compounds (i.e. baicalein, luteolin, N-nornuciferine, roemerine, scutellarin, and 6-shogaol). In parallel assays, a six-compound combo (SCC) and Banxia-Houpo decoction markedly ameliorated the depressive-like behaviors in corticosterone-lesioned mice and well-protected highly differentiated (HD) PC12 cells against corticosterone challenge. Moreover, six-compound combo and Banxia-Houpo decoction effectively induced hydroxytryptamine receptor 1A expression in mice and postsynaptic microglia BV2 cells. Hydroxytryptamine receptor 1A antagonist WAY-100635 at 1 mg/kg/d via intraperitoneal injection attenuated the effects of six-compound combo and Banxia-Houpo decoction on the depressive behaviors in mice. These results suggest that six-compound combo might be a potential remedy against depression and other neurological disorders via targeting hydroxytryptamine receptor 1A in microglia.