| Summary: | Major depressive disorder (MDD) is one life-threatening disorder that is prevalent worldwide. The evident etiology of this disease is still poorly understood. Currently, herbal medicine is gaining more interest as an alternative antidepressant. <i>Oroxylum indicum</i>, which is used in traditional medicine and contains a potential antidepressive compound, baicalein, could have an antidepressive property. An <i>in vitro</i> monoamine oxidase-A (MAO-A) inhibitory assay was used to preliminarily screening for the antidepressant effect of <i>O. indicum</i> seed (<i>OIS</i>) extract. Mice were subjected to unpredictable chronic mild stress (UCMS) for 6 weeks, and the daily administration of <i>OIS</i> extract started from week 4. The mechanisms involved in the antidepressive activity were investigated. The <i>OIS</i> extract significantly alleviated anhedonia and despair behaviors in the UCMS-induced mouse model via two possible pathways: (i) it normalized the HPA axis function via the restoration of negative feedback (decreased FKBP5 and increased GR expressions) and the reduction in the glucocorticoid-related negative gene (SGK-1), and (ii) it improved neurogenesis via the escalation of BDNF and CREB expressions in the hippocampus and the frontal cortex. In addition, an HPLC analysis of the <i>OIS</i> extract showed the presence of baicalin, baicalein, and chrysin as major constituents. All of the results obtained from this study emphasize the potential of <i>OIS</i> extract containing baicalin and baicalein as an effective and novel alternative treatment for MDD.
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