Exploring the neurofunctional potential of saffron bioactives: from mood-related behavioral modulation to brain access of safranal

Saffron (Crocus sativus L.) has long been recognized for its mood-enhancing properties. However, the precise contribution and neurobiological mechanisms of its main active compounds, crocins and safranal, remain underexplored, despite their potential to improve the management of mood disorders. This preclinical study compared their antidepressant-like effects alongside their impact on key neurobiological systems involved in mood regulation. Additionally, it assessed safranal's oral bioavailability, which was previously unknown. C57BL/6J mice received an acute oral dose of crocins (250 µg kg^-1) or safranal (75 µg kg^-1), corresponding to the respective amounts present in the saffron extract Safr'Inside™ at the dose previously used in preclinical studies, 30 min before behavioral assessment. Dopaminergic function was evaluated via quantification of dopamine and its metabolites by HPLC-ECD, combined with RT-qPCR analysis of related receptors and transporters, while kynurenine pathway activation was assessed through mRNA expression of its key enzymes in the prefrontal cortex and striatum. Both compounds reduced depressive-like behavior, albeit with distinct response patterns. Crocins primarily modulated the dopaminergic system, whereas safranal selectively downregulated neurotoxic components of the kynurenine pathway, shifting its neurotoxic/neuroprotective balance to promote neuroprotection. In parallel, serum and brain concentrations of safranal were measured at 15 and 30 min after oral administration of increasing doses, using a newly developed and validated UHPLC-DAD-MS/MS method. This allowed, for the first time, the detection of safranal in both serum and the brain following a single administration using a validated analytical method. Altogether, these findings provide novel and valuable insights into the disposition of safranal following oral administration and the distinct neurobiological mechanisms of saffron bioactives, highlighting their complementary roles and supporting their relevance as functional agents for mood-related disorders.