Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms

The prevalence of depressive disorders is growing worldwide, notably due to stagnation in the development of drugs with greater antidepressant efficacy, the continuous large proportion of patients who do not respond to conventional antidepressants, and the increasing rate of chronic medical conditions associated with an increased vulnerability to depressive comorbidities. Accordingly, better knowledge on the pathophysiology of depression and mechanisms underlying depressive comorbidities in chronic medical conditions appears urgently needed, in order to help in the development of targeted therapeutic strategies. In this review, we present evidence pointing to inflammatory processes as key players in the pathophysiology and treatment of depressive symptoms. In particular, we report preclinical and clinical findings showing that inflammation-driven alterations in specific metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, leads to substantial alterations in the metabolism of serotonin, glutamate and dopamine that are likely to contribute to the development of key depressive symptom dimensions. Accordingly, anti-inflammatory interventions targeting kynurenine and BH4 pathways may be effective as novel treatment or as adjuvants of conventional medications rather directed to monoamines, notably when depressive symptomatology and inflammation are comorbid in treated patients. This notion is discussed in the light of recent findings illustrating the tight interactions between known antidepressant drugs and inflammatory processes, as well as their therapeutic implications. Altogether, this review provides valuable findings for moving toward more adapted and personalized therapeutic strategies to treat inflammation-related depressive symptoms

Modulation of gut microbiota by antibiotics did not affect anhedonia in a high-fat diet-induced model of depression in male mice

Long-term consumption of a high-fat diet (HFD) causes obesity and is a risk factor for depression. HFD has a significant impact on the gut microbiota, and dysbiosis of the microbiota is now associated with certain psychiatric disorders such as anxiety and depression. We aimed to investigate whether modulation by antibiotic treatment of the composition of the gut microbiota in diet-induced obese (DIO) mice has an impact on depressive-like behavior. In this study, we analyzed the effects of a 15 weeks HFD consumption by male mice on their depressive-like behavior assessed in the forced swim and sucrose preference tests. Two weeks before beginning the behavioral tests, a group of DIO mice were given a combination of two non-absorbable antibiotics, neomycin and polymyxin B. HFD induced anhedonia, as revealed by the sucrose preference test, and significant changes in gut microbiota composition at the phyla and family levels. On the other hand, there was no significant effect of HFD on the peripheral and brain inflammatory profiles. In DIO mice treated with the antibiotics, an even more pronounced alteration in the composition of the gut microbiota occurred, without any change in anhedonia behavior. Only four families of bacteria were not affected in their abundance by the antibiotic treatment, the Rikenellaceae, Streptococcaceae, Erysipelotrichaceae and Bifidobacteriaceae. This stability concomitant with that of anhedonia may suggest that these families were involved in this depression-like behavior

Tetrahydrobiopterin improves recognition memory in the triple-transgenic mouse model of Alzheimer's disease, without altering amyloid-β and tau pathologies

*Background: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. *Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-beta (A beta) neuropathologies associated with behavior impairment. *Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. *Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3 xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on A beta and tau neuropathologies. *Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.IdEx BordeauxProgram Initiative d’Excellenc

Dietary intake of branched-chain amino acids in a mouse model of Alzheimer's disease: Effects on survival, behavior, and neuropathology

Introduction High levels of plasmatic branched-chain amino acids (BCAA), commonly used as dietary supplements, are linked to metabolic risk factors for Alzheimer's disease (AD). BCAA directly influence amino acid transport to the brain and, therefore, neurotransmitter levels. We thus investigated the impact of BCAA on AD neuropathology in a mouse model. Methods 3xTg-AD mice were fed either a control diet or a high-fat diet from 6 to 18 months of age. For the last 2 months, dietary BCAA content was adjusted to high (+50%), normal (+0%), or low (−50%). Results Mice fed a BCAA-supplemented high-fat diet displayed higher tau neuropathology and only four out of 13 survived. Mice on the low-BCAA diet showed higher threonine and tryptophan cortical levels while performing better on the novel object recognition task. Discussion These preclinical data underscore a potential risk of combining high-fat and high BCAA consumption, and possible benefits from BCAA restriction in AD

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

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

DHA involvement in neurotransmission process

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Le point sur les AGPI omega 3 et 6 : implication dans le fonctionnement cérébral

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Association Hyper Super, TDAH et AGPI omega 3 : quelles recherches ?

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Oméga 3 et neurotransmission cérébrale

Les acides gras polyinsaturés (AGPI) sont des constituants structuraux fondamentaux du système nerveux central (SNC) dont la teneur conditionne le fonctionnement des cellules neuronales. Ils sont des acteurs de la communication intercellulaire, notamment à travers les processus de neurotransmission. De nombreuses études ont montré chez l’animal que le déficit des membranes cérébrales en oméga 3, et plus particulièrement en acide docosahexaénoïque (22 : 6ω-3 ou DHA) induit par une carence alimentaire spécifique en cette famille d’AGPI, s’accompagne de troubles de l’apprentissage. Un support neurochimique a été avancé, impliquant les processus de libération de neurotransmetteurs, notamment les monoamines et l’acétylcholine. Cette relation entre AGPI ω3 et neurotransmission est d’autant plus intéressante qu’elle pourrait être également impliquée chez l’Homme dans l’apparition et\\ou la sévérité de certains troubles neuropsychiatriques dans lesquels des dysfonctionnements de la neurotransmission sont constatés (schizophrénie, dépression, hyperactivité chez l’enfant). En effet, de nombreuses études révèlent un déficit du statut corporel en AGPI oméga 3 (20 : 5 et 22 : 6) mais aussi en oméga 6, qui peut être corrigé par voie nutritionnelle, permettant alors de réduire significativement certains des symptômes pathologiques. Dans ce contexte, nous développons au laboratoire des recherches visant à comprendre les mécanismes d’action des oméga 3, et en particulier du DHA, dans les membranes nerveuses et l’incidence sur le fonctionnement de ces cellules