17 research outputs found

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

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    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

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

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    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

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

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    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

    Depressive disorders and therapeutic response : underlying mechanisms and nutritional modulation by saffron active ingredients (Crocus sativus L.).

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    Les troubles dépressifs représentent un problème majeur de santé publique dont l’incidence ne cesse d’augmenter dans le monde. Ceci peut s’expliquer par le taux croissant d’individus ne répondant pas aux traitements antidépresseurs (ADs) conventionnels, mais également par la recrudescence de pathologies, souvent à composante inflammatoire, connues pour être associées à un risque accru de comorbidités neuropsychiatriques. De plus, une large proportion de patients déprimés développe des effets secondaires fortement invalidants. Ces problèmes soulignent la nécessité d'identifier des stratégies alternatives aux traitements pharmaceutiques actuels. L'utilisation d’interventions nutritionnelles peut alors être une solution de premier choix. En effet, certains nutriments et extraits de plantes ont des propriétés bioactives et peuvent ainsi moduler de nombreux systèmes neurobiologiques, dont ceux impliqués dans la physiopathologie des troubles dépressifs, tout en réduisant les effets secondaires. Dans ce contexte, le safran représente un candidat prometteur dans la prévention et le traitement des troubles dépressifs. En effet, des études cliniques et précliniques ont déjà montré une amélioration de la symptomatologie dépressive après administration d’actifs de safran, mais les mécanismes sous-tendant ces propriétés bénéfiques sont encore largement inconnus. Mieux les comprendre est pourtant essentiel afin de valider la pertinence thérapeutique d’interventions nutritionnelles avec des extraits de safran. En outre, il est important d’identifier les personnes qui pourraient être les plus à même d’en bénéficier. Les patients présentant une faible réponse thérapeutique aux ADs classiques pourraient alors être les premiers concernés. Diverses données récentes suggèrent l’implication de processus inflammatoires non seulement dans le développement des troubles dépressifs, mais aussi dans la mauvaise réponse aux ADs. Dès lors, cibler l'inflammation apparait comme une stratégie de choix pour améliorer la réponse clinique. De manière intéressante, plusieurs études ont mis en évidence des propriétés immunomodulatrices du safran, suggérant qu’il pourrait améliorer la réponse thérapeutique chez les patients dépressifs présentant un profil inflammatoire. Dans ce contexte, l’objectif général de ce travail de thèse a donc été de préciser le rôle d’interventions nutritionnelles basées sur des apports en safran dans la prise en charge des troubles dépressifs et d’en déterminer quels en sont les mécanismes. Pour cela, nous avons dans un premier temps mis en évidence les effets bénéfiques du safran sur les comportements de type dépressif induits notamment dans des conditions modélisant différents facteurs de risque de la dépression, tels que le stress. Les résultats neurobiologiques obtenus suggèrent qu’il agirait en ciblant en particulier les systèmes monoaminergiques centraux et la voie de la kynurénine. Dans un second temps, nous avons validé une approche expérimentale innovante basée sur l’utilisation de deux modèles murins de dépression différant par leurs mécanismes physiopathologiques, notamment en ce qui concerne les processus inflammatoires et permettant ainsi d’en étudier l’implication dans le développement et le traitement des troubles dépressifs. En conclusion, ce travail de thèse a permis d’établir des preuves précliniques de l’efficacité d’un extrait de safran dans la prise en charge des troubles dépressifs et de commencer à élucider les mécanismes d’action impliqués. Il a également validé une approche expérimentale adaptée à l’étude approfondie des mécanismes sous-jacents à la dépression inflammatoire, et qui devrait, à terme, permettre de mieux caractériser les populations susceptibles de bénéficier des approches nutritionnelles, en substitution ou en complément des traitements pharmaceutiques, sur la base de leur profil clinique. Ces travaux devraient donc contribuer à améliorer la prise en charge et le traitement des troubles dépressifs.Depressive disorders are a major public health concern and display a rising prevalence worldwide. This effect can be explained by the increasing rate of individuals not responding to conventional antidepressant (ADs) treatments, but also by the rise of chronic conditions, often associated with low-grade inflammation and known to be associated with an increased risk of neuropsychiatric comorbidities. Moreover, a large proportion of depressed patients develop highly disabling side effects. These issues highlight the need to identify alternative strategies to current pharmaceutical treatments and the use of nutritional interventions may be a first-choice solution. Indeed, some nutrients and plant extracts have bioactive properties and can modulate many neurobiological systems, including those involved in the pathophysiology of depressive disorders, while reducing side effects. In that context, saffron therefore represents a promising candidate for the prevention and treatment of depressive disorders. Indeed, clinical and preclinical studies already reported improved depressive symptomatology after administration of saffron active compounds, although the mechanisms underlying these beneficial properties are still largely unknown. Better understanding those mechanisms is however essential in order to validate the therapeutic relevance of nutritional interventions with saffron extracts. In addition, it is important to identify the individuals who may be most likely to benefit from those interventions. Patients with a poor therapeutic response to conventional ADs may thus be the first concerned. Recent data suggest the involvement of inflammatory processes not only in the development of depressive disorders, but also in the poor response to ADs. Therefore, targeting inflammation appears to be a promising strategy to improve clinical response. Interestingly, several studies have demonstrated the immunomodulatory properties of saffron, suggesting that it may be particularly relevant to improve the therapeutic response in depressed patients with an inflammatory profile. In that context, the general objective of this thesis was therefore to clarify the role of nutritional interventions based on saffron supplementation in the management of depressive disorders and to determine the underlying mechanisms. For this purpose, we first demonstrated the beneficial effects of saffron on depressive-like behaviors, particularly in conditions modeling various risk factors for depression, such as stress. The neurobiological results suggest that it may act by particularly targeting central monoaminergic systems and the kynurenine pathway. In a second step, we validated an experimental strategy using two murine models of depression with different pathophysiological mechanisms, particularly regarding inflammatory processes, thus enabling to study their involvement in the development and treatment of depressive disorders. In conclusion, this thesis work allowed to establish preclinical evidence of the efficacy of a saffron extract in the management of depressive disorders and to start elucidating the underlying mechanisms. It also allowed to validate an experimental approach adapted to the in-depth study of the mechanisms underlying inflammatory depression and which should in turn help to better characterize the populations likely to benefit from nutritional approaches, as a replacement for or complement to pharmaceutical treatments, on the basis of their clinical profile. Taken together, this work should therefore contribute to improve the management and treatment of depressive disorders

    Troubles dépressifs et réponse thérapeutique : mécanismes d'action et modulation nutritionnelle par des actifs de safran (Crocus sativus L.).

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    Depressive disorders are a major public health concern and display a rising prevalence worldwide. This effect can be explained by the increasing rate of individuals not responding to conventional antidepressant (ADs) treatments, but also by the rise of chronic conditions, often associated with low-grade inflammation and known to be associated with an increased risk of neuropsychiatric comorbidities. Moreover, a large proportion of depressed patients develop highly disabling side effects. These issues highlight the need to identify alternative strategies to current pharmaceutical treatments and the use of nutritional interventions may be a first-choice solution. Indeed, some nutrients and plant extracts have bioactive properties and can modulate many neurobiological systems, including those involved in the pathophysiology of depressive disorders, while reducing side effects. In that context, saffron therefore represents a promising candidate for the prevention and treatment of depressive disorders. Indeed, clinical and preclinical studies already reported improved depressive symptomatology after administration of saffron active compounds, although the mechanisms underlying these beneficial properties are still largely unknown. Better understanding those mechanisms is however essential in order to validate the therapeutic relevance of nutritional interventions with saffron extracts. In addition, it is important to identify the individuals who may be most likely to benefit from those interventions. Patients with a poor therapeutic response to conventional ADs may thus be the first concerned. Recent data suggest the involvement of inflammatory processes not only in the development of depressive disorders, but also in the poor response to ADs. Therefore, targeting inflammation appears to be a promising strategy to improve clinical response. Interestingly, several studies have demonstrated the immunomodulatory properties of saffron, suggesting that it may be particularly relevant to improve the therapeutic response in depressed patients with an inflammatory profile. In that context, the general objective of this thesis was therefore to clarify the role of nutritional interventions based on saffron supplementation in the management of depressive disorders and to determine the underlying mechanisms. For this purpose, we first demonstrated the beneficial effects of saffron on depressive-like behaviors, particularly in conditions modeling various risk factors for depression, such as stress. The neurobiological results suggest that it may act by particularly targeting central monoaminergic systems and the kynurenine pathway. In a second step, we validated an experimental strategy using two murine models of depression with different pathophysiological mechanisms, particularly regarding inflammatory processes, thus enabling to study their involvement in the development and treatment of depressive disorders. In conclusion, this thesis work allowed to establish preclinical evidence of the efficacy of a saffron extract in the management of depressive disorders and to start elucidating the underlying mechanisms. It also allowed to validate an experimental approach adapted to the in-depth study of the mechanisms underlying inflammatory depression and which should in turn help to better characterize the populations likely to benefit from nutritional approaches, as a replacement for or complement to pharmaceutical treatments, on the basis of their clinical profile. Taken together, this work should therefore contribute to improve the management and treatment of depressive disorders.Les troubles dépressifs représentent un problème majeur de santé publique dont l’incidence ne cesse d’augmenter dans le monde. Ceci peut s’expliquer par le taux croissant d’individus ne répondant pas aux traitements antidépresseurs (ADs) conventionnels, mais également par la recrudescence de pathologies, souvent à composante inflammatoire, connues pour être associées à un risque accru de comorbidités neuropsychiatriques. De plus, une large proportion de patients déprimés développe des effets secondaires fortement invalidants. Ces problèmes soulignent la nécessité d'identifier des stratégies alternatives aux traitements pharmaceutiques actuels. L'utilisation d’interventions nutritionnelles peut alors être une solution de premier choix. En effet, certains nutriments et extraits de plantes ont des propriétés bioactives et peuvent ainsi moduler de nombreux systèmes neurobiologiques, dont ceux impliqués dans la physiopathologie des troubles dépressifs, tout en réduisant les effets secondaires. Dans ce contexte, le safran représente un candidat prometteur dans la prévention et le traitement des troubles dépressifs. En effet, des études cliniques et précliniques ont déjà montré une amélioration de la symptomatologie dépressive après administration d’actifs de safran, mais les mécanismes sous-tendant ces propriétés bénéfiques sont encore largement inconnus. Mieux les comprendre est pourtant essentiel afin de valider la pertinence thérapeutique d’interventions nutritionnelles avec des extraits de safran. En outre, il est important d’identifier les personnes qui pourraient être les plus à même d’en bénéficier. Les patients présentant une faible réponse thérapeutique aux ADs classiques pourraient alors être les premiers concernés. Diverses données récentes suggèrent l’implication de processus inflammatoires non seulement dans le développement des troubles dépressifs, mais aussi dans la mauvaise réponse aux ADs. Dès lors, cibler l'inflammation apparait comme une stratégie de choix pour améliorer la réponse clinique. De manière intéressante, plusieurs études ont mis en évidence des propriétés immunomodulatrices du safran, suggérant qu’il pourrait améliorer la réponse thérapeutique chez les patients dépressifs présentant un profil inflammatoire. Dans ce contexte, l’objectif général de ce travail de thèse a donc été de préciser le rôle d’interventions nutritionnelles basées sur des apports en safran dans la prise en charge des troubles dépressifs et d’en déterminer quels en sont les mécanismes. Pour cela, nous avons dans un premier temps mis en évidence les effets bénéfiques du safran sur les comportements de type dépressif induits notamment dans des conditions modélisant différents facteurs de risque de la dépression, tels que le stress. Les résultats neurobiologiques obtenus suggèrent qu’il agirait en ciblant en particulier les systèmes monoaminergiques centraux et la voie de la kynurénine. Dans un second temps, nous avons validé une approche expérimentale innovante basée sur l’utilisation de deux modèles murins de dépression différant par leurs mécanismes physiopathologiques, notamment en ce qui concerne les processus inflammatoires et permettant ainsi d’en étudier l’implication dans le développement et le traitement des troubles dépressifs. En conclusion, ce travail de thèse a permis d’établir des preuves précliniques de l’efficacité d’un extrait de safran dans la prise en charge des troubles dépressifs et de commencer à élucider les mécanismes d’action impliqués. Il a également validé une approche expérimentale adaptée à l’étude approfondie des mécanismes sous-jacents à la dépression inflammatoire, et qui devrait, à terme, permettre de mieux caractériser les populations susceptibles de bénéficier des approches nutritionnelles, en substitution ou en complément des traitements pharmaceutiques, sur la base de leur profil clinique. Ces travaux devraient donc contribuer à améliorer la prise en charge et le traitement des troubles dépressifs

    Depressive disorders and therapeutic response : underlying mechanisms and nutritional modulation by saffron active ingredients (Crocus sativus L.).

    No full text
    Les troubles dépressifs représentent un problème majeur de santé publique dont l’incidence ne cesse d’augmenter dans le monde. Ceci peut s’expliquer par le taux croissant d’individus ne répondant pas aux traitements antidépresseurs (ADs) conventionnels, mais également par la recrudescence de pathologies, souvent à composante inflammatoire, connues pour être associées à un risque accru de comorbidités neuropsychiatriques. De plus, une large proportion de patients déprimés développe des effets secondaires fortement invalidants. Ces problèmes soulignent la nécessité d'identifier des stratégies alternatives aux traitements pharmaceutiques actuels. L'utilisation d’interventions nutritionnelles peut alors être une solution de premier choix. En effet, certains nutriments et extraits de plantes ont des propriétés bioactives et peuvent ainsi moduler de nombreux systèmes neurobiologiques, dont ceux impliqués dans la physiopathologie des troubles dépressifs, tout en réduisant les effets secondaires. Dans ce contexte, le safran représente un candidat prometteur dans la prévention et le traitement des troubles dépressifs. En effet, des études cliniques et précliniques ont déjà montré une amélioration de la symptomatologie dépressive après administration d’actifs de safran, mais les mécanismes sous-tendant ces propriétés bénéfiques sont encore largement inconnus. Mieux les comprendre est pourtant essentiel afin de valider la pertinence thérapeutique d’interventions nutritionnelles avec des extraits de safran. En outre, il est important d’identifier les personnes qui pourraient être les plus à même d’en bénéficier. Les patients présentant une faible réponse thérapeutique aux ADs classiques pourraient alors être les premiers concernés. Diverses données récentes suggèrent l’implication de processus inflammatoires non seulement dans le développement des troubles dépressifs, mais aussi dans la mauvaise réponse aux ADs. Dès lors, cibler l'inflammation apparait comme une stratégie de choix pour améliorer la réponse clinique. De manière intéressante, plusieurs études ont mis en évidence des propriétés immunomodulatrices du safran, suggérant qu’il pourrait améliorer la réponse thérapeutique chez les patients dépressifs présentant un profil inflammatoire. Dans ce contexte, l’objectif général de ce travail de thèse a donc été de préciser le rôle d’interventions nutritionnelles basées sur des apports en safran dans la prise en charge des troubles dépressifs et d’en déterminer quels en sont les mécanismes. Pour cela, nous avons dans un premier temps mis en évidence les effets bénéfiques du safran sur les comportements de type dépressif induits notamment dans des conditions modélisant différents facteurs de risque de la dépression, tels que le stress. Les résultats neurobiologiques obtenus suggèrent qu’il agirait en ciblant en particulier les systèmes monoaminergiques centraux et la voie de la kynurénine. Dans un second temps, nous avons validé une approche expérimentale innovante basée sur l’utilisation de deux modèles murins de dépression différant par leurs mécanismes physiopathologiques, notamment en ce qui concerne les processus inflammatoires et permettant ainsi d’en étudier l’implication dans le développement et le traitement des troubles dépressifs. En conclusion, ce travail de thèse a permis d’établir des preuves précliniques de l’efficacité d’un extrait de safran dans la prise en charge des troubles dépressifs et de commencer à élucider les mécanismes d’action impliqués. Il a également validé une approche expérimentale adaptée à l’étude approfondie des mécanismes sous-jacents à la dépression inflammatoire, et qui devrait, à terme, permettre de mieux caractériser les populations susceptibles de bénéficier des approches nutritionnelles, en substitution ou en complément des traitements pharmaceutiques, sur la base de leur profil clinique. Ces travaux devraient donc contribuer à améliorer la prise en charge et le traitement des troubles dépressifs.Depressive disorders are a major public health concern and display a rising prevalence worldwide. This effect can be explained by the increasing rate of individuals not responding to conventional antidepressant (ADs) treatments, but also by the rise of chronic conditions, often associated with low-grade inflammation and known to be associated with an increased risk of neuropsychiatric comorbidities. Moreover, a large proportion of depressed patients develop highly disabling side effects. These issues highlight the need to identify alternative strategies to current pharmaceutical treatments and the use of nutritional interventions may be a first-choice solution. Indeed, some nutrients and plant extracts have bioactive properties and can modulate many neurobiological systems, including those involved in the pathophysiology of depressive disorders, while reducing side effects. In that context, saffron therefore represents a promising candidate for the prevention and treatment of depressive disorders. Indeed, clinical and preclinical studies already reported improved depressive symptomatology after administration of saffron active compounds, although the mechanisms underlying these beneficial properties are still largely unknown. Better understanding those mechanisms is however essential in order to validate the therapeutic relevance of nutritional interventions with saffron extracts. In addition, it is important to identify the individuals who may be most likely to benefit from those interventions. Patients with a poor therapeutic response to conventional ADs may thus be the first concerned. Recent data suggest the involvement of inflammatory processes not only in the development of depressive disorders, but also in the poor response to ADs. Therefore, targeting inflammation appears to be a promising strategy to improve clinical response. Interestingly, several studies have demonstrated the immunomodulatory properties of saffron, suggesting that it may be particularly relevant to improve the therapeutic response in depressed patients with an inflammatory profile. In that context, the general objective of this thesis was therefore to clarify the role of nutritional interventions based on saffron supplementation in the management of depressive disorders and to determine the underlying mechanisms. For this purpose, we first demonstrated the beneficial effects of saffron on depressive-like behaviors, particularly in conditions modeling various risk factors for depression, such as stress. The neurobiological results suggest that it may act by particularly targeting central monoaminergic systems and the kynurenine pathway. In a second step, we validated an experimental strategy using two murine models of depression with different pathophysiological mechanisms, particularly regarding inflammatory processes, thus enabling to study their involvement in the development and treatment of depressive disorders. In conclusion, this thesis work allowed to establish preclinical evidence of the efficacy of a saffron extract in the management of depressive disorders and to start elucidating the underlying mechanisms. It also allowed to validate an experimental approach adapted to the in-depth study of the mechanisms underlying inflammatory depression and which should in turn help to better characterize the populations likely to benefit from nutritional approaches, as a replacement for or complement to pharmaceutical treatments, on the basis of their clinical profile. Taken together, this work should therefore contribute to improve the management and treatment of depressive disorders

    J Neuroinflammation

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    Major depressive disorder (MDD) represents a major public health concern, particularly due to its steadily rising prevalence and the poor responsiveness to standard antidepressants notably in patients afflicted with chronic inflammatory conditions, such as obesity. This highlights the need to improve current therapeutic strategies, including by targeting inflammation based on its role in the pathophysiology and treatment responsiveness of MDD. Nevertheless, dissecting the relative contribution of inflammation in the development and treatment of MDD remains a major issue, further complicated by the lack of preclinical depression models suitable to experimentally dissociate inflammation-related vs. inflammation-unrelated depression. While current models usually focus on one particular MDD risk factor, we compared in male C57BL/6J mice the behavioral, inflammatory and neurobiological impact of chronic exposure to high-fat diet (HFD), a procedure known to induce inflammation-related depressive-like behaviors, and unpredictable chronic mild stress (UCMS), a stress-induced depression model notably renowned for its responsivity to antidepressants. While both paradigms induced neurovegetative, depressive-like and anxiety-like behaviors, inflammation and downstream neurobiological pathways contributing to inflammation-driven depression were specifically activated in HFD mice, as revealed by increased circulating levels of inflammatory factors, as well as brain expression of microglial activation markers and enzymes from the kynurenine and tetrahydrobiopterin (BH4) pathways. In addition, serotoninergic and dopaminergic systems were differentially impacted, depending on the experimental condition. These data validate an experimental design suitable to deeply study the mechanisms underlying inflammation-driven depression comparatively to non-inflammatory depression. This design could help to better understand the pathophysiology of treatment resistant depression.Role of inflammation and related processes in the development, phenomenology and treatment of depressio

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

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    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

    Depression and therapeutic resistance: complementary models to study inflammatory versus non-inflammatory depression in mice

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    PosterDepression represents a major public health concern. Its prevalence is continuously rising, notably in patients exposed to chronic stress or suffering from medical conditions associated with low-grade chronic inflammation, such as obesity. These patients also often display increased resistance to conventional antidepressants (AD). There is growing evidence that inflammation plays a role in depressive disorders. Interestingly, recent clinical findings suggest that it may also contribute to therapeutic resistance, although the underlying mechanisms are still poorly understood. A relevant preclinical model of depression allowing to assess the specific features of inflammation is therefore urgently needed. The present study aims to model inflammatory vs. non-inflammatory depression in mice. To address this issue, we compared depressive-like behaviors and peripheral and brain inflammation in mice exposed to diet-induced obesity (DIO) (60% Kcal from fat, 6 months from weaning), a procedure known to induce inflammation, or to unpredictable chronic mild stress (UCMS, 7 weeks), known to induce depressive-like behaviors responding to classical antidepressants. Peripheral inflammation was assessed by measuring plasma concentrations of inflammatory factors by bioplex. Both DIO and UCMS induce depressive-like behaviors, as indicated by increased coat state score, latency to feed in the novelty suppressed feeding test, and immobility in the forced swim test. In contrast, systemic inflammation is only detected in DIO mice, as revealed by higher plasma concentrations of cytokines and chemokines, such as interleukins 6 and 10 (IL-6, IL-10), interferon gamma induced protein 10 (IP-10) and interferon gamma induced monokine (MIG). Detailed analysis of associated activation of brain inflammatory processes is still in progress, but the present data suggest that the preclinical approach reported here can be useful to deeply study the mechanisms underlying inflammation-driven depression and therapeutic resistance, comparatively to non-inflammatory depression
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