Antidepressant effects of sulforaphane (SFN) and its derivatives SLL-III-9 and SLL-III-120 and their potential underlying mechanisms based on the microbiota-gut-brain axis.

Broccoli ( Brassica oleracea L.) is a vegetable with numerous nutritional properties, with sulforaphane (SFN) being the most abundant and unique bioactive ingredient. SFN has anti-inflammatory, antioxidant, and anti-cancer activities. In this study, a series of SFN derivatives were synthesized and screened for improved antidepressant effects. Among these, the SFN derivatives SLL-III-9 and SLL-III-120 were the best candidates, and the potential antidepressant mechanism of SFN, SLL-III-9, and SLL-III-120 associated with their effects in a chronic unpredictable mild stress (CUMS) mouse model was explored based on the microbiota-gut-brain axis. All three compounds were able to relieve depression-like behaviors in CUMS mice and regulate the composition of the gut bacteria Firmicutes, Actinobacteria, Parabasalia, and Tenericutes at the phylum level and Bacteroidales bacterium , Lachnospiraceae bacterium A4 , Muribaculum intestinale , Muribaculaceae bacterium , and Prevotella sp. MGM1 at the species level, possibly altering their function associated with the anti-inflammatory effect. Additionally, SFN and its derivatives upregulated the expression of the tight junction proteins ZO-1, occludin, and claudin and increased the concentration of IL-10, dopamine (DA), 5-hydroxytryptamine (5-HT) and the brain-derived neurotrophic factor (BDNF), while downregulating the expressions of proteins related to the NF-κB/NLRP3 pathway and reducing the concentration of TNF-α. Further in vitro studies revealed significant inhibition of the production of inflammatory factors IL-1β, IL-18, IL-6, and TNF-α in LPS-activated BV2 cells via the NF-κB/NLRP3 pathway when these cells were treated with SFN or its two derivatives. Taken together, the results suggested that SFN and its two derivatives, SLL-III-9 and SLL-III-120, could be considered potential compounds for the development of a promising and safe agent for combating depression.