Saffron Extract-Induced Improvement of Depressive-Like Behavior in Mice Is Associated with Modulation of Monoaminergic Neurotransmission

Depressive disorders represent a major public health concern and display a continuously rising prevalence. Importantly, a large proportion of patients develops aversive side effects and/or does not respond properly to conventional antidepressants. These issues highlight the need to identify further therapeutic strategies, including nutritional approaches using natural plant extracts with known beneficial impacts on health. In that context, growing evidence suggests that saffron could be a particularly promising candidate. This preclinical study aimed therefore to test its antidepressant-like properties in mice and to decipher the underlying mechanisms by focusing on monoaminergic neurotransmission, due to its strong implication in mood disorders. For this purpose, the behavioral and neurobiochemical impact of a saffron extract, Safr’Inside™ (6.5 mg/kg per os) was measured in naïve mice. Saffron extract reduced depressive-like behavior in the forced swim test. This behavioral improvement was associated with neurobiological modifications, particularly changes in serotonergic and dopaminergic neurotransmission, suggesting that Safr’Inside™ may share common targets with conventional pharmacological antidepressants. This study provides useful information on the therapeutic relevance of nutritional interventions with saffron extracts to improve management of mood disorders

Dietary (Poly)phenols and the Gut–Brain Axis in Ageing

As the population ages, the incidence of age-related neurodegenerative diseases is rapidly increasing, and novel approaches to mitigate this soaring prevalence are sorely needed. Recent studies have highlighted the importance of gut microbial homeostasis and its impact on brain functions, commonly referred to as the gut–brain axis, in maintaining overall health and wellbeing. Nonetheless, the mechanisms by which this system acts remains poorly defined. In this review, we will explore how (poly)phenols, a class of natural compounds found in many plant-based foods and beverages, can modulate the gut–brain axis, and thereby promote neural health. While evidence indicates a beneficial role of (poly)phenol consumption as part of a balanced diet, human studies are scarce and mechanistic insight is still lacking. In this regard, we make the case that dietary (poly)phenols should be further explored to establish their therapeutic efficacy on brain health through modulation of the gut–brain axis, with much greater emphasis on carefully designed human interventions

Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice

Ageing is characterised by memory deficits, associated with brain plasticity impairment. Polyphenols from berries, such as flavan-3-ols, anthocyanins, and resveratrol, have been suggested to modulate synaptic plasticity and cognitive processes. In the present study we assessed the preventive effect of a polyphenol-rich extract from grape and blueberry (PEGB), with high concentrations of flavonoids, on age-related cognitive decline in mice. Adult and aged (6 weeks and 16 months) mice were fed a PEGB-enriched diet for 14 weeks. Learning and memory were assessed using the novel object recognition and Morris water maze tasks. Brain polyphenol content was evaluated with ultra-high-performance LC-MS/MS. Hippocampal neurotrophin expression was measured using quantitative real-time PCR. Finally, the effect of PEGB on adult hippocampal neurogenesis was assessed by immunochemistry, counting the number of cells expressing doublecortin and the proportion of cells with dendritic prolongations. The combination of grape and blueberry polyphenols prevented age-induced learning and memory deficits. Moreover, it increased hippocampal nerve growth factor (Ngf) mRNA expression. Aged supplemented mice displayed a greater proportion of newly generated neurons with prolongations than control age-matched mice. Some of the polyphenols included in the extract were detected in the brain in the native form or as metabolites. Aged supplemented mice also displayed a better survival rate. These data suggest that PEGB may prevent age-induced cognitive decline. Possible mechanisms of action include a modulation of brain plasticity. Post-treatment detection of phenolic compounds in the brain suggests that polyphenols may act directly at the central level, while they can make an impact on mouse survival through a potential systemic effect

Nutrients

According to animal studies, saffron and its main volatile compound safranal may reduce biological and behavioral signs of acute stress. However, little is known about its impact in humans. This study investigated the acute effect of a saffron extract and safranal on the biological and psychological stress responses in healthy men experiencing a laboratory stress procedure. In this double-blind, placebo-controlled, randomized, cross-over study, 19 volunteers aged 18-25 received a single dose of 30 mg saffron extract (Safr'Inside, 0.06 mg synthetic safranal, or a placebo on three visits separated by a 28-day washout. Thirteen minutes after administration, participants were exposed to the Maastricht acute stress test (MAST). Salivary cortisol and cortisone were collected from 15 min before the MAST (and pre-dose), 3 min before the MAST, and then 15, 30, 45, 60, and 75 min after the MAST, and stress and anxiety were measured using visual analogic scales. Compared to the placebo, stress and anxiety were significantly toned down after Safranal and Safr'Inside administration and coupled with a delay in the times to peak salivary cortisol and cortisone concentrations ( < 0.05). Safr'Inside and its volatile compound seem to improve psychological stress response in healthy men after exposure to a lab-based stressor and may modulate the biological stress response

Front Psychol

Polyphenols are naturally occurring organic compounds found in plants. Research suggests that their intake reduces the risk of cognitive decline and related dementias. Grapes and blueberries are polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Examine the effects of supplementation with a standardized and patented polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment. Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. One hundred and forty-three volunteers aged 60 to 80 years with mild cognitive impairment were supplemented with either 150 mg of Memophenol™, twice daily or a placebo. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function (BRIEF-A), the Cognitive Failures Questionnaire, and the CASP-19. Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing ( = 0.020), visuospatial learning ( = 0.012), and the BRIEF-A global score ( = 0.046). However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires. Memophenol™ supplementation was well-tolerated with no reports of significant adverse reactions. The promising results from this trial suggest that 6-months of supplementation with Memophenol™ may improve aspects of cognitive function in adults with mild cognitive impairment. Further research will be important to expand on the current findings and identify the potential mechanisms of action associated with the intake of this polyphenol-rich extract

Pattern of polyphenol intake and the long-term risk of dementia in older persons

International audienc

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

Treatment of anxiety and depression predominantly centres around pharmacological interventions, which have faced criticism for their associated side effects, lack of efficacy and low tolerability. Saffron, which is reportedly well tolerated in humans, has been recognised for its antidepressant and anti-anxiety properties. Indeed, we previously reported upon the efficacy of saffron extract supplementation in healthy adults with subclinical anxiety. However, the molecular aetiology remains unclear. In a rodent model of low-grade chronic inflammation, we explored the impact of a saffron extract (Safr’InsideTM) supplementated at a physiological dose, which equated to 22 ± 1.2 mg per day human equivalent dose for a person of 60 Kg. Behavioural tests (Open field task, Y maze, Novel object recognition), caecal 16S rRNA microbial sequencing, caecal 1H NMR metabolomic analysis and 2DE brain proteomic analyses were completed to probe gut-brain axis interactions. Time occupying the centre of the Open field maze (OF) was increased by 62% in saffron supplemented animals. This improvement in anxiety-related behaviour coincided with gut microbial shifts, notably Akkermansia, Muribaculaceae, Christensenellacae and Alloprevotella which significantly increased in response to saffron supplementation. Akkermansia and Muribaculaceae abundance negatively correlated with the neurotoxic metabolite dimethylamine which was reduced in saffron supplemented animals. Brain proteomic analysis highlighted several significantly altered proteins including ketimine reductase mu-crystallin which also correlated with dimethylamine concentration. Both dimethylamine and ketimine reductase mu-crystallin were associated with OF performance. This may be indicative of a novel interaction across the gut-brain axis which contributes to anxiety-related disorders

Saffron extract interferes with lipopolysaccharide-induced brain activation of the kynurenine pathway and impairment of monoamine neurotransmission in mice

BackgroundAlthough activation of inflammatory processes is essential to fight infections, its prolonged impact on brain function is well known to contribute to the pathophysiology of many medical conditions, including neuropsychiatric disorders. Therefore, identifying novel strategies to selectively counter the harmful effects of neuroinflammation appears as a major health concern. In that context, this study aimed to test the relevance of a nutritional intervention with saffron, a spice known for centuries for its beneficial effect on health.MethodsFor this purpose, the impact of an acute oral administration of a standardized saffron extract, which was previously shown to display neuromodulatory properties and reduce depressive-like behavior, was measured in mice challenged with lipopolysaccharide (LPS, 830 μg/kg, ip).ResultsPretreatment with saffron extract (6.5 mg/kg, per os) did not reduce LPS-induced sickness behavior, preserving therefore this adaptive behavioral response essential for host defense. However, it interfered with delayed changes of expression of cytokines, chemokines and markers of microglial activation measured 24 h post-LPS treatment in key brain areas for behavior and mood control (frontal cortex, hippocampus, striatum). Importantly, this pretreatment also counteracted by that time the impact of LPS on several neurobiological processes contributing to inflammation-induced emotional alterations, in particular the activation of the kynurenine pathway, assessed through the expression of its main enzymes, as well as concomitant impairment of serotonergic and dopaminergic neurotransmission.ConclusionAltogether, this study provides important clues on how saffron extract interferes with brain function in conditions of immune stimulation and supports the relevance of saffron-based nutritional interventions to improve the management of inflammation-related comorbidities

Effects of saffron extract supplementation on mood, well-being, and response to a psychosocial stressor in healthy adults: A randomized, double-blind, parallel group, clinical trial

Anxiety, stress, and low mood are closely related and may contribute to depressive symptoms. Among non-pharmacological solutions to improve subclinical mood symptoms and resilience to stress, natural products such as saffron—identified as promising following preliminary beneficial effects in major depressive disorder—represent a relevant strategy. This study aimed to assess the efficacy of 8 weeks' supplementation with 30 mg standardized saffron extract on emotional well-being in healthy adults with subclinical feelings of low mood and anxiety and/or stress and evaluate the acute effect of saffron in response to a lab-based psychosocial stressor. The study adopted a double-blind, randomized, parallel groups design in which 56 healthy male and female individuals (18–54 years) received either a saffron extract or a placebo for 8 weeks. Chronic effects of saffron on subjective anxiety, stress, and depressive feelings were assessed using a questionnaire battery [including Profile of Mood State-2, (POMS)] and acute effects in response to a lab-based psychosocial stressor were measured through psychological and physiological parameters. Urinary crocetin levels were quantified. Participants who received the saffron extract reported reduced depression scores and improved social relationships at the end of the study. Urinary crocetin levels increased significantly with saffron supplementation and were correlated with change in depression scores. The typical stress-induced decrease in heart rate variability (HRV) during exposure to the stressor was attenuated following acute saffron intake. Saffron extract appears to improve subclinical depressive symptoms in healthy individuals and may contribute to increased resilience against the development of stress-related psychiatric disorders. Clinical trials number: NCT03639831

Circulating human serum metabolites derived from the intake of a saffron extract (Safr’Inside™) protect neurons from oxidative stress: Consideration for depressive disorders

Increases in oxidative stress have been reported to play a central role in the vulnerability to depression, and antidepressant drugs may reduce increased oxidative stress in patients. Among the plants exerting anti-inflammatory and anti-oxidant properties, saffron, a spice derived from the flower of Crocus sativus, is also known for its positive effects on depression, potentially through its SSRI-like properties. However, the molecular mechanisms underlying these effects and their health benefits for humans are currently unclear. Using an original ex vivo clinical approach, we demonstrated for the first time that the circulating human metabolites produced following saffron intake (Safr’Inside™ ) protect human neurons from oxidative-stress-induced neurotoxicity by preserving cell viability and increasing BNDF production. In particular, the metabolites significantly stimulated both dopamine and serotonin release. In addition, the saffron’s metabolites were also able to protect serotonergic tone by inhibiting the expression of the serotonin transporter SERT and down-regulating serotonin metabolism. Altogether, these data provide new biochemical insights into the mechanisms underlying the beneficial impact of saffron on neuronal viability and activity in humans, in the context of oxidative stress related to depression