The allyl isothiocyanate (AITC) isolated from mustard (Sinapis alba L.) oil exerts antidepressant effects by blocking the interaction between SERT and nNOS

Ethnopharmacological relevance: Mustard, derived from the dried mature seeds of Sinapis alba L (Cruciferae family), is known for its characteristic pungency, primarily attributed to mustard oil (MO). MO have traditionally been used to invigorate the spirit and relieve emotional distress. Growing evidence suggests its potential as an adjunctive therapy for mental disorders, however, the specific active compounds and their molecular mechanisms underlying these antidepressant-like effects remain unclear.

Aim of the study: To identify the bioactive substances and elucidate their pharmacological mechanisms of MO in the treatment of depression.

Methods and results: Using mouse models of chronic social defeat stress (CSDS) and chronic restraint stress (CRS), we confirmed the antidepressant effect of MO through behavioral assessments. GC-MS analysis identified four candidate compounds in MO, among which allyl isothiocyanate (AITC) was determined to be the most potent contributor to its antidepressant activity via NanoBRET-based targeting NOS-SERT interaction. To improve its aqueous solubility and bioavailability, an AITC microemulsion (AITC ME) was developed via the pseudo-ternary phase diagram approach. The resulting AITC ME was transparent, exhibited uniform droplet size, and demonstrated robust stability. We employed behavioral tests, functional magnetic resonance imaging (fMRI), and electrophysiological recordings to comprehensively evaluate the pharmacodynamic profile and mechanism of action of the AITC ME. The results revealed that the AITC ME not only produced rapid-onset antidepressant effects but also prolonged the duration of efficacy. Mechanistic investigations suggested that AITC disrupts the protein interaction between SERT and nNOS in the dorsal raphe nucleus, leading to enhanced membrane localization of SERT. Additionally, it improved functional connectivity among brain regions implicated in depression, activated serotonergic neurons in the DRN, increased their firing rate, and subsequently enhanced serotonin release in both the prefrontal cortex and hippocampus, collectively contributing to its antidepressant effects.

Conclusion: These findings suggest AITC ME as a promising candidate for rapid-onset antidepressant development, warranting further investigation into its translational potential.

Allyl isothiocyanate; Antidepressant effect; Negative feedback; Neuronal nitric oxide synthase; Serotonin transporter; mustard oil.