Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

Abstract

Depressive disorders are a major public health concern. Despite currently available treatment options, their prevalence steadily increases, and a high rate of therapeutic failure is often reported, together with important antidepressant-related side effects. This highlights the need to improve existing therapeutic strategies, including by using nutritional interventions. In that context, saffron recently received particular attention for its beneficial effects on mood, although the underlying mechanisms are poorly understood. This study investigated in mice the impact of a saffron extract (Safr’Inside™; 6.25 mg/kg, per os) on acute restraint stress (ARS)-induced depressive-like behavior and related neurobiological alterations, by focusing on hypothalamic–pituitary–adrenal axis, inflammation-related metabolic pathways, and monoaminergic systems, all known to be altered by stress and involved in depressive disorder pathophysiology. When given before stress onset, Safr’Inside administration attenuated ARS-induced depressive-like behavior in the forced swim test. Importantly, it concomitantly reversed several stress-induced monoamine dysregulations and modulated the expression of key enzymes of the kynurenine pathway, likely reducing kynurenine-related neurotoxicity. These results show that saffron pretreatment prevents the development of stress-induced depressive symptoms and improves our understanding about the underlying mechanisms, which is a central issue to validate the therapeutic relevance of nutritional interventions with saffron in depressed patients.

Saffron extract (Safr'Inside™) improves anxiety related behaviour in a mouse model of low-grade inflammation through the modulation of the microbiota and gut derived metabolites

“…Saffron, obtained from the dried stigmas of Crocus sativus 21 has been reported to have anti-anxiety and anti-depressant properties as determined by us and others in both preclinical 22–24 and clinical trials. 25–27 Regarded as safe/well-tolerated, the effectiveness of saffron in the treatment of both anxiety and depression appears comparable to that of pharmaceutical intervention.…”

“…Despite these positive reports emphasising saffron's anti-anxiety/depressive properties, the mechanistic picture remains incomplete. Of the limited evidence available, saffron's anti-inflammatory properties are most frequently cited, 28 along with modulation of the monoaminergic neurotransmission 22,23 and oxidative stress, 27 indicating that these mechanisms may be an integral part of the process. Despite evidence of saffron-mediated gut microbial shift, 29,30 this has not been explored in the context of mental health/anxiety.…”

The role of saffron (Crocus sativus L) on testosterone and depression in andropause middle-aged and elderly men: a systematic review

“…(2) The effect of saffron on testosterone levels and depression severity in middle-aged and elderly animals has been studied in six studies (Modaresi et al, 2008;Orio et al, 2020;Vafaei et al, 2020;Alaei et al, 2014;Monchaux De Oliveira et al, 2021a, 2021b. Table 2.…”

Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

“…Another recent study also supported the role of Kyn in depression’s associated neuroinflammation. Saffron administration in mice attenuated inflammation-related metabolic pathways and modulated the expression of Kyn-related neurotoxicity, attenuating depressive-like behaviors in these animals [ 56 ]. Furthermore, the administration of the anti-inflammatory herb Radix Polygalae to mice exposed to chronic restraint stress led to modulation of inflammation, microbiota, and Trp/Kyn metabolism.…”