| Summary: | Menopause is a risk factor for depression. Although 1,3-dicaffeoylquinic acid (1,3-diCQA), a phenolic compound in <i>Arctium lappa</i> (<i>A. lappa</i>) root, has various health benefits, its effects on menopausal depression remain to be determined. Therefore, this study investigates the antidepressant-like effects of 1,3-diCQA from an <i>A. lappa</i> root extract (AE) and the associated molecular mechanisms. Ovariectomized (OVX) mice were orally administered AE for 20 weeks, following which depression-like behaviors were assessed. Although the mice exhibited depression-like behaviors, AE administration mitigated these symptoms by activating the ERK–CREB–BDNF pathway and increasing nNOS levels in the hippocampus. Similarly, a significant increase in nNOS-derived NO production and activation of the ERK–CREB–BDNF pathway was observed in the primary hippocampal neurons. Although this stimulatory effect of 1,3-diCQA was not significantly affected by treatment with estrogen receptor agonist or antagonist, it was inhibited by 7-NI, an nNOS inhibitor. Moreover, mice treated with 1,3-diCQA exhibited a marked improvement in their forced swimming test and tail suspension test immobility, while pretreatment with 7-NI reversed the antidepressant-like effects of 1,3-diCQA. Our results suggest that 1,3-diCQA regulates nNOS in an estrogen recepters-independent manner to increase NO production in OVX mice.
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