Anxiolytic and Antidepressant Effects of Organic Polysulfide, Dimethyl Trisulfide Are Partly Mediated by the Transient Receptor Potential Ankyrin 1 Ion Channel in Mice

Dimethyl trisulfide (DMTS) is a naturally occurring organic polysulfide associated with protective functions such as antioxidant and neuroprotective effects. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression‐like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model exposed to chronic unpredictable mild stress (CUMS), we examined the impact of DMTS on depression‐like behaviour and anxiety, and identified the involved brain regions. Our methods involved testing both Trpa1 wild‐type and gene‐knockout mice under CUMS conditions and DMTS treatment. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression‐like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB immunohistochemistry was utilized to assess chronic neuronal activation in stress‐ relevant brain areas. Results showed that CUMS induces depression‐like behaviour in a TRPA1‐ dependent manner and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic‐pituitary‐ adrenal (HPA) axis dysregulation. Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1‐mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety.