Plant Extracts and ω-3 Improve Short-Term Memory and Modulate the Microbiota-Gut-Brain Axis in D-galactose Model Mice.

BACKGROUND: Aging, characterized by a slow and progressive alteration of cognitive functions, is associated with gut microbiota dysbiosis, low-grade chronic inflammation, as well as increased oxidative stress and neurofunctional alterations. Some nutrients, such as polyphenols, carotenoids, and omega (ω)-3 (n-3), are good candidates to prevent age-related cognitive decline, because of their immunomodulatory, antioxidant, and neuroprotective properties. OBJECTIVES: The objective of this study was to demonstrate the preventive effect of a combination of plant extracts (PE) containing Memophenol™ (grapes and blueberries polyphenols) and a patented saffron extract (saffron carotenoids and safranal) and ω-3 on cognitive function in a mouse model of accelerated aging and to understand the biological mechanisms involved. METHODS: We used an accelerated-aging model by injecting 3-mo-old male C57Bl6/J mice with D-galactose for 8 wk, during which they were fed with a balanced control diet and supplemented or not with PE and/or ω-3 (n = 15-16/group). Short-term memory was evaluated by Y-maze test, following analyses of hippocampal and intestinal RNA expressions, brain fatty acid and oxylipin amounts, and gut microbiota composition (16S rRNA gene sequencing). Statistical analyses were performed (t test, analysis of variance, and Pearson correlation). RESULTS: Our results showed that oral administration of PE, ω-3, or both (mix) prevented hippocampus-dependent short-term memory deficits induced by D-galactose (P < 0.05). This effect was accompanied by the modulation of gut microbiota, altered by the treatment. PE and the mix increased the expression of antioxidative and neurogenesis markers, such as catalase and doublecortin, in hippocampus (P < 0.05 for both). Moreover, ω-3 and the mix showed a higher ω-3 amounts (P < 0.05) and EPA-derived 18- hydroxyeicosapentaenoic acid (P < 0.001) in prefrontal cortex. These changes may contribute to the improvement in memory. CONCLUSIONS: These results suggest that the mix of PE and ω-3 could be more efficient at attenuating age-related cognitive decline than individual supplementations because it targeted, in mice, the different pathways impaired with aging.

Plant extracts and omega-3 supplementation modulate hippocampal oxylipin profile in response to LPS-induced neuroinflammation.

OBJECTIVE AND DESIGN: Neuroinflammation is a protective mechanism but can become harmful if chronic and/or unregulated, leading to neuronal damage and cognitive alterations. Limiting inflammation and promoting resolution could be achieved with nutrients such as grapes and blueberries polyphenols, saffron carotenoids, and omega-3, which have anti-inflammatory and proresolutive properties. METHODS: This study explored the impact of 18-day supplementation with plant extracts (grape, blueberry and saffron), omega-3 or both (mix) on neuroinflammation induced by lipopolysaccharide (LPS, 250 µg/kg) in 149 mice at different time points post-LPS treatment (30 min, 2 h, 6 h). Inflammatory, oxidative and neuroprotective gene expression; oxylipin quantification; and fatty acid composition were analyzed at each time point. PCA analysis was performed with all these biomarkers. RESULTS: Mix supplementation induced changes in the resolution of inflammation. In fact, the production of proinflammatory mediators in the hippocampus started earlier in the supplemented group than in the LPS group. Pro-resolving mediators were also found in higher quantities in supplemented mice. These changes were associated with increased hippocampal antioxidant status at 6 h post-LPS. CONCLUSIONS: These findings suggest that such dietary interventions with plant extracts, and omega-3 could be beneficial in preventing neuroinflammation and, consequently, age-related cognitive decline. Further research is needed to explore the effects of these supplements on chronic inflammation in the context of aging.

Authentication of Iranian Saffron (Crocus sativus) Using Stable Isotopes δ13C and δ2H and Metabolites Quantification.

Saffron is a very high value-added ingredient used in the food supplement market and contains a high level of safranal. Adding synthetic safranal to saffron, which is significantly cheaper, and falsifying the origin of saffron may represent recurrent fraud. Saffron from different countries was analyzed to determine the stable isotope ratios δ13C and δ2H from safranal by gas chromatography coupled with isotope-ratio mass spectrometry (GC-C/P-IRMS) and the concentration of saffron metabolites with ultra-high performance liquid chromatography coupled with diode array detector (UHPLC-DAD). The isotopic analysis highlighted a higher ratio of δ2H in synthetic safranal than in natural safranal; the mean values were 36‱ (+/- 40) and -210‱ (+/- 35), respectively. The δ13C between Iranian, Spanish and other saffron was significantly different and represents median values of -28.62‱, -30.12‱ and -30.70‱, respectively. Moreover, linear and quadratic discriminant analyses (LDA and QDA) were computed using the two isotope ratios of safranal and the saffron metabolites. A first QDA showed that trans-crocetin and the δ13C of safranal, picrocrocin, and crocin C3 concentrations clearly differentiated Iranian saffron from other origins. A second model identified δ13C, trans-crocetin, crocin C2, crocin C3, and picrocrocin as good predictors to discriminate saffron samples from Iran, Spain, or other origins, with a total ability score classification matrix of 100% and a prediction matrix of 82.5%. This combined approach may be a useful tool to authenticate the origin of unknown saffron.

A mixed grape and blueberry extract is safe for dogs to consume.

BACKGROUND: Grape and blueberry extracts are known to protect against age-related cognitive decline. However, beneficial effects achieved by mixing grape and blueberry extracts have yet to be evaluated in dogs, or their bioavailability assessed. Of concern to us were cases of acute renal failure in dogs, after their ingestion of grapes or raisins. The European Pet Food Industry Federation (2013) considers only the grape or raisin itself to be potentially dangerous; grape-seed extracts per-se, are not considered to be a threat. Our aim was therefore to evaluate the renal and hepatic safety, and measure plasma derivatives of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) in dogs. Polyphenol expression was analyzed by UHPLC-MS/MS over 8 hours, for dogs given PEGB at 4 mg/kg. Safety was evaluated using four groups of 6 dogs. These groups received capsules containing no PEGB (control), or PEGB at 4, 20, or 40 mg/kg BW/d, for 24 weeks. Blood and urine samples were taken the week prior to study commencement, then at the end of the 24-wk study period. Routine markers of renal and liver damage, including creatinine (Creat), blood urea nitrogen, albumin, minerals, alkaline phosphatase (ALP), and alanine transaminase (ALT) were measured. Biomarkers for early renal damage were also evaluated in plasma (cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL)), and urine (CysC, clusterin (Clu), and NGAL). Ratios of urinary biomarkers to Creat were calculated, and compared with acceptable maximal values obtained for healthy dogs, as reported in the literature. RESULTS: While several PEGB-specific polyphenols and metabolites were detected in dog plasma, at the end of the PEGB consumption period, our biomarker analyses presented no evidence of either renal or liver damage (Creat, BUN, ionogram, albumin and ALT, ALP). Similarly, no indication of early renal damage could be detected. Plasma CysC, urinary CysC/Creat, Clu/Creat, and NGAL/Creat ratios were all beneath reported benchmarked maximums, with no evidence of PEGB toxicity. CONCLUSIONS: Long-term consumption of a pet specific blend of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium), was not associated with renal or hepatic injury, and can therefore be considered safe.

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.

(Poly)phenol-rich grape and blueberry extract prevents LPS-induced disruption of the blood-brain barrier through the modulation of the gut microbiota-derived uremic toxins.

The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.

Characterization of Crocetin Isomers in Serum Samples via UHPLC-DAD-MS/MS and NMR after Saffron Extract (Safr'Inside™) Consumption.

The therapeutic effects of saffron have been reported and described in relation to its major derivatives. Among them, in terms of saffron's properties, crocin and crocetin absorption and bioavailability have been the most studied. Nevertheless, the metabolism of these major compounds of saffron has not yet been entirely elucidated. Current data indicate that the phase 2 metabolism of crocetins go through conjugation reactions. Crocetins could also be present in isomeric forms such as other carotenoids. Nonetheless, there are still shadow areas in regard to the measurements of the different circulating forms of crocetins after oral saffron extract administration (Safr'Inside™). In using various approaches, we propose the identification of a new cis isomeric form of crocetin, the 6-cis-crocetin. This compound was found in human serum samples after an oral administration of saffron extract. The 6-cis-crocetin represents 19% of the total crocetin measured after 45 min of consumption. These data mark, for the first time, the presence of a cis isomeric form of crocetin in human serum samples. Moreover, this study led to the development of an analytical method that is able to identify and quantify both isomeric forms (trans and cis).

A novel Mediterranean diet-inspired supplement ameliorates cognitive, microbial, and metabolic deficits in a mouse model of low-grade inflammation.

The Mediterranean diet (MD) and its bioactive constituents have been advocated for their neuroprotective properties along with their capacity to affect gut microbiota speciation and metabolism. Mediated through the gut brain axis, this modulation of the microbiota may partly contribute to the neuroprotective properties of the MD. To explore this potential interaction, we evaluated the neuroprotective properties of a novel bioactive blend (Neurosyn240) resembling the Mediterranean diet in a rodent model of chronic low-grade inflammation. Behavioral tests of cognition, brain proteomic analysis, 16S rRNA sequencing, and 1H NMR metabolomic analyses were employed to develop an understanding of the gut-brain axis interactions involved. Recognition memory, as assessed by the novel object recognition task (NOR), decreased in response to LPS insult and was restored with Neurosyn240 supplementation. Although the open field task performance did not reach significance, it correlated with NOR performance indicating an element of anxiety related to this cognitive change. Behavioral changes associated with Neurosyn240 were accompanied by a shift in the microbiota composition which included the restoration of the Firmicutes: Bacteroidota ratio and an increase in Muribaculum, Rikenellaceae Alloprevotella, and most notably Akkermansia which significantly correlated with NOR performance. Akkermansia also correlated with the metabolites 5-aminovalerate, threonine, valine, uridine monophosphate, and adenosine monophosphate, which in turn significantly correlated with NOR performance. The proteomic profile within the brain was dramatically influenced by both interventions, with KEGG analysis highlighting oxidative phosphorylation and neurodegenerative disease-related pathways to be modulated. Intriguingly, a subset of these proteomic changes simultaneously correlated with Akkermansia abundance and predominantly related to oxidative phosphorylation, perhaps alluding to a protective gut-brain axis interaction. Collectively, our results suggest that the bioactive blend Neurosyn240 conferred cognitive and microbiota resilience in response to the deleterious effects of low-grade inflammation.

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake.

Safe and anti-inflammatory plant-based natural products present an increasing focus in the treatment of chronic inflammatory diseases such as osteoarthritis or inflammatory bowel diseases. Among them, saffron, a spice derived from the stigma of Crocus sativus, could have anti-inflammatory properties and would be therefore a promising therapeutic agent for the treatment of such conditions. However, the anti-inflammatory molecular mechanisms of saffron in humans are still understudied and unclear. In this study, combining human serum metabolites and cell cultures, we evaluated the effect of circulating metabolites from the consumption of a patented saffron extract (Safr'InsideTM) on the chondrocytes and colon epithelial cell responses to inflammatory stress. Parametric or non-parametric Analysis of Variance with post hoc tests was performed. We demonstrated that human serum containing metabolites from saffron intake attenuated IL-1ß-stimulated production of PGE2 and MMP-13 in chondrocyte cells and limited the increase in ICAM-1, MCP-1, iNOS, and MMP-3 in human epithelial cells following combined IL-1ß and TNF-α inflammatory stimulation. Altogether, these data provide new findings into the mechanisms underlying the beneficial effects of saffron on chondrocytes and enterocyte cells at the cellular level and in the context of chronic inflammatory disorders.

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

Background: Although 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. Methods: For 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). Results: Pretreatment 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. Conclusion: Altogether, 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 a polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study.

Background: 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. Purpose: 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. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Methods: 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. Results: Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing (p = 0.020), visuospatial learning (p = 0.012), and the BRIEF-A global score (p = 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. Conclusion: 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.

Plasma carotenoids and risk of depressive symptomatology in a population-based cohort of older adults.

BACKGROUND: As part of a healthy diet, higher carotenoid intakes have been associated with a reduced risk of depression, mainly in adults, while prospective studies on plasma carotenoids in older adults are lacking. The aim of this study was to assess the prospective association between plasma carotenoids and the risk of Depressive Symptomatology (DS) in older adults. METHODS: The study sample was based on the Three-City cohort of adults aged 65y+ free from DS at enrollment in 1999. Plasma carotenoids were measured at baseline. DS was assessed every 2-3 years over 17 years and defined by a Center for Epidemiologic Studies-Depression Scale score ≥ 16 and/or by antidepressant use. The association between plasma carotenoids or carotenoid/lipids (cholesterol and triglycerides) ratio and the risk for DS was assessed through multiple random-effect logistic regression. RESULTS: The study sample was composed of 1010 participants (mean age 74 y (±4.9), 58 % of women) followed-up during a median time of 13.4 years. Plasma zeaxanthin and ratios of zeaxanthin/lipids, lutein+zeaxanthin/lipids and ß-carotene/lipids were independently associated with a significant reduced risk of DS over time (Odds ratio (OR) = 0.81, 95 % Confidence Interval (CI) [0.67;0.99], OR = 0.79 [0.67;0.98], OR = 0.79 [0.64;0.94] and OR = 0.80 [0.66;0.97] for +1 standard deviation of each exposure respectively). LIMITATIONS: Plasma carotenoids were only available at study baseline. CONCLUSION: Focusing on circulating carotenoids and considering lipids levels, the present results suggested an association between higher levels of plasma zeaxanthin, combined lutein+zeaxanthin and ß-carotene and a decreased risk of DS over time in older adults.

Acute Effect of a Saffron Extract (Safr'InsideTM) and Its Main Volatile Compound on the Stress Response in Healthy Young Men: A Randomized, Double Blind, Placebo-Controlled, Crossover Study.

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'InsideTM), 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'InsideTM administration and coupled with a delay in the times to peak salivary cortisol and cortisone concentrations (p < 0.05). Safr'InsideTM 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.

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.

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'Inside™) supplemented 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.

Patterns of polyphenol intake and risk of depressive symptomatology in a population-based cohort of older adults.

BACKGROUND & AIMS: Current evidence suggests that some isolated polyphenols (PP) may exert promising effects for the risk of depression in young adults, however studies among older adults remain limited. The aim of the current study was to examine the prospective association between patterns of PP intake and the risk of depressive symptomatology (DS) in older adults. METHODS: The study sample was based on the Three-City (3C) Bordeaux cohort of adults aged 65 years and over and without DS at the time of recruitment. The intakes of PP, summarised into 21 PP classes, were determined using a 24-h recall combined with the Phenol-Explorer database. In addition, the patterns of PP intake were identified by a Principal Component Analysis (PCA). DS was evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D) over a period of 15 years with a reassessment every 2-3 years. The incident DS was reported for CES-D score ≥16 and/or the use of antidepressant treatment. The association between the patterns of PP intake at baseline and the risk of DS was computed using multivariate random-effect logistic regression models. RESULTS: Among the 1074 participants (mean age 75.7 y, SD 4.8 y), 423 (39.4%) developed a DS during the follow-up. Distinct patterns of PP intake were identified, explaining up to 50% of the variance. The two first patterns, mainly driven by stilbenes and dihydroflavonols and by hydroxyicnnamic acid and alkylmethoxyphenols respectively, were not associated with the odds of DS. Furthermore, a higher score on the third pattern, mainly driven by monomeric flavanols and theaflavins, was associated with a significant 27% lower risk of DS over time (Odd Ratio = 0.73, 95% Confidence Interval [0.55; 0.97]). CONCLUSION: This prospective study suggested that a pattern high in monomeric flavanols and theaflavins intakes, mainly provided by tea, was associated with a reduced risk of DS in older adults. These results provide promising evidence on combined PP intakes that would require further confirmation in other samples.

Circulating Human Serum Metabolites Derived from the Intake of a Saffron Extract (Safr'InsideTM) 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'InsideTM) 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.

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.

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

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.

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.

Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study.

Polyphenols are promising nutritional bioactives exhibiting beneficial effect on age-related cognitive decline. This study evaluated the effect of a polyphenol-rich extract from grape and blueberry (PEGB) on memory of healthy elderly subjects (60-70 years-old). A bicentric, randomized, double-blind, placebo-controlled trial was conducted with 215 volunteers receiving 600 mg/day of PEGB (containing 258 mg flavonoids) or a placebo for 6 months. The primary outcome was the CANTAB Paired Associate Learning (PAL), a visuospatial learning and episodic memory test. Secondary outcomes included verbal episodic and recognition memory (VRM) and working memory (SSP). There was no significant effect of PEGB on the PAL on the whole cohort. Yet, PEGB supplementation improved VRM-free recall. Stratifying the cohort in quartiles based on PAL at baseline revealed a subgroup with advanced cognitive decline (decliners) who responded positively to the PEGB. In this group, PEGB consumption was also associated with a better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. Urinary concentrations of specific flavan-3-ols metabolites were associated, at the end of the intervention, with the memory improvements. Our study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments.