Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

Omega-3 (omega-3) and omega-6 (omega-6) are polyunsaturated fatty acids (PUFAs) that play critical role in human health and have to be provided by food. In the brain, PUFAs are also precursors of endocannabinoids. The aim of this chapter is to review the existing literature on how dietary PUFAs impact on the endocannabinoid system in the brain and what are the consequences for brain function and dysfunction. In this chapter, we will first describe how PUFAs enter the brain, what are their metabolism processes and roles in brain function. We will describe the pathways from PUFAs to endocannabinoid production. Then, we will review the literature on how dietary omega-6/omega-3 ratio impacts the endocannabinoid system, in terms of endocannabinoid levels, proteins and endocannabinoid-dependent synaptic plasticity. In the next part, we will describe what we know about the interactions between PUFAs and endocannabinoids in neurological and neuropsychiatric disorders. Finally, we will conclude on the possible implications of the interactions between dietary PUFAs and endocannabinoids in the normal and pathological brain. In particular, we will discuss how dietary PUFAs, as homeostatic regulators of endocannabinoids, can constitute interesting therapeutic strategies for the prevention and/or treatment of neurological disorders with endocannabinoids impairment.FP7-267196-MSCA-COFUND-AgreenSkill

Role of neuroinflammation in the emotional and cognitive alterations displayed by animal models of obesity

Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

Le développement d’approches nutritionnelles pertinentes pour prévenir et retarder l’apparition du déclin cognitif est un enjeu important, compte tenu du vieillissement de la population et de l’augmentation de l’incidence des maladies neurodégénératives. Les processus neuro-inflammatoires contribuent aux mécanismes neuropathologiques impliqués dans les troubles neurodégénératifs et de la cognition. Des données récentes indiquent l’importance des acides gras polyinsaturés n-3 alimentaires dans le maintien des performances mnésiques et la régulation de la neuroinflammation liée à l’âge ou à la maladie d’Alzheimer. Dans cette revue, seront présentées des données récentes sur les liens existants entre le statut nutritionnel en acides gras polyinsaturés n-3, les processus neuro-inflammatoires et les troubles cognitifs associés, ainsi que les mécanismes qui pourraient être impliqués dans les effets protecteurs de ces acides gras.With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new nutritional approaches to prevent and delay the onset of cognitive decline. Neuroinflammatory processes contribute to neuronal damage that underpins neurodegenerative disorders. Growing evidence sheds light on the use of dietary n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in cognitive disorders. We will also discuss the mechanisms underlying n-3 polyunsaturated fatty acids effect on neuroinflammation and memory decline

Front Nutr

Nutrition is now well recognized to be an environmental factor which positively or negatively influences the risk to develop neurological and psychiatric disorders. The gut microbiota has recently been shown to be an important actor mediating the relationship between environmental factors, including nutrition, and brain function. While its composition has been widely studied and associated with the risk of brain diseases, the mechanisms underlying the relationship between the gut and brain diseases remain to be explored. The wide range of bioactive molecules produced by the gut microbiota, called gut-derived metabolites (GDM), represent new players in the gut to brain interactions and become interesting target to promote brain health. The aim of this narrative review is to highlight some GDMs of interest that are produced in response to healthy food consumption and to summarize what is known about their potential effects on brain function. Overall, GDMs represent future useful biomarkers for the development of personalized nutrition. Indeed, their quantification after nutritional interventions is a useful tool to determine individuals' ability to produce microbiota-derived bioactive compounds upon consumption of specific food or nutrients. Moreover, GDMs represent also a new therapeutic approach to counteract the lack of response to conventional nutritional interventions.Risk factors and markers for early detection of Alzheimer's Disease: focus on early-life adversity, inflammation and lipid mediatorsMetabolic profiling of the gut-brain axis as a new stratification process to improve behavioural disorders: proof of concept in alcohol dependenc

Nutrigenomic modification induced by anthocyanin-rich bilberry extract in the hippocampus of ApoE-/- mice

Dietary anthocyanins may slow cognitive decline, improve cognitive performance and exert neuroprotective effects against neurodegenerative disorders. However, the underlying mechanisms of their action are not fully understood. This study investigated the effects of 12-week anthocyanin-rich bilberry extract supplementation (0.02%) on global gene expression in the hippocampus of ApoE-/- mice to help the understanding of molecular mechanisms underlying anthocyanin neuroprotective effects. Gene expression analysis identified 1698 differently expressed genes, with 611 downregulated and 1087 upregulated genes. Bioinformatics revealed that these genes regulate different biological processes, including neurogenesis, inflammation, metabolism, cell to cell adhesion, cytoskeleton organization, and Alzheimer's and Parkinson's disease pathology. The bioinformatic analysis also proposed potential miRNAs and transcription factors that could be involved in the mediation of these nutrigenomic effects. Results from molecular docking also suggested that anthocyanins could bind to top transcription factors with, as potential consequence, an impact on their gene expression regulation. Taken together, integrated analysis revealed a multi-target mode of action of anthocyanin-rich bilberry extract in the hippocampus underlying their neuroprotective properties

How nutrients and natural products act on the brain: Beyond pharmacology

Understanding how natural products promote brain health is key to designing diverse strategies to improve the lives of people with, or at risk of developing, neurodegenerative disorders. The mechanisms of action involved and recent technological progress are discussed.Metabolic profiling of the gut-brain axis as a new stratification process to improve behavioural disorders: proof of concept in alcohol dependenceRisk factors and markers for early detection of Alzheimer's Disease: focus on early-life adversity, inflammation and lipid mediator

Role of n-3 PUFAs in inflammation via resolvin biosynthesis

Le rôle des AGPI n-3 a considérablement augmenté ces dernières années, en particulier dans les processus inflammatoires en raison de leurs propriétés anti-inflammatoires. L’inflammation est une réponse protectrice de l’organisme visant à contrôler l’infection et à favoriser la réparation des tissus. Cependant, une inflammation excessive peut avoir de graves conséquences au niveau des tissus. C’est notamment le cas pour le cerveau pour lequel les conséquences fonctionnelles de la neuro-inflammation comprennent des altérations de la cognition, de l’affect et du comportement, conduisant à un impact négatif sur la qualité de vie et le bien-être des patients (Dantzer, 2001, 2008). Par conséquent, limiter l’inflammation dans le cerveau représente une véritable stratégie dans le cadre de la prévention et du traitement des maladies neuro-inflammatoires. Des données récentes montrent que les AGPI n-3 exercent leurs propriétés anti-inflammatoires en partie via la synthèse de médiateurs lipidiques spécialisés tels que les résolvines, qui participent activement à réduire la réponse inflammatoire. Cette revue rappelle d’abord les concepts de base de la réponse inflammatoire et le rôle des AGPI n-3 dans ce processus et présente ensuite la biosynthèse, les voies de signalisation et le rôle des résolvines.The role of n-3 PUFAs has gained more importance these last decades, especially in inflammatory processes because they can display anti-inflammatory properties. Inflammation is a protective response of the body in controlling infection and promoting tissue repair. However, excessive inflammation can cause local tissue damage. This is especially the case for the brain for which the functional consequences of neuroinflammation include alterations in cognition, affect and behavior leading to a negative impact on the quality of life and well-being of patients (Dantzer, 2001, 2008). Hence, limiting the inflammation in the brain is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators such as resolvins that actively turned off the inflammatory response. This review first outlines basic concepts of neuroinflammation and the role of n-3 PUFAs in this process and then summarizes the biosynthesis, signaling pathways and role of resolvins

n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging

Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging

The interest of adding micronutrients to docosahexaenoic acid supplementation to prevent age--related cognitive decline

Aging is associated to cognitive decline that can lead to neurodegenerative diseases and constitutes one of the main social and economic issues of the 21st century. The loss of memory, orientation and processing abilities associated with aging are involved in the loss of autonomy and in the decline in the quality of life in the elderly. Brain structures involved in memory such as hippocampus, cortex and striatum, are particularly affected by molecular and cellular damage during this period. Lipid metabolism and neurofunctional alterations, including disturbances in synaptic plasticity and neurogenesis, chronic low-grade inflammation and increased oxidative stress, are partly to be involved in age-related cognitive decline. Actually, nutrition represents a strategy of choice to prevent or delay these impairments since many studies have provided valuable data concerning the effect of dietary patterns and specific nutrients on cognitive function. From all nutrients, some of them are particularly attractive. Indeed, n-3 polyunsaturated acids (PUFAs), especially docosahexaenoic acid (DHA), have been identified for their beneficial effects on cognition, notably by acting on brain plasticity (synaptic plasticity, neurogenesis), neuroinflammation and oxidative stress. Other nutrients such as vitamin A, vitamin E, vitamin D, polyphenols as well as pre- and probiotics have aroused a growing interest in decreasing cognitive disorders. As nutrition has to be taken as a whole, we first described the effects of the Mediterranean diet which constitutes the most complete association of nutrients and (DHA from fish, vitamins and polyphenols from fruits and vegetables) represents a global vision of nutrition, then we focused on the interest of combining DHA and micronutrients contained in this diet as well as pre- and probiotics, to prevent age-related cognitive decline and reported the synergistic effects of these associations. Finally, we completed with benefits from dairy products that increase DHA incorporation

Nutritional omega-3 deficiency alters glucocorticoid receptor-signaling pathway and neuronal morphology in regionally distinct brain structures associated with emotional deficits

Extensive evidence suggests that long term dietary n-3 polyunsaturated fatty acids (PUFAs) deficiency results in altered emotional behaviour. We have recently demonstrated that n-3 PUFAs deficiency induces emotional alterations through abnormal corticosterone secretion which leads to altered dendritic arborisation in the prefrontal cortex (PFC). Here we show that hypothalamic-pituitary-adrenal (HPA) axis feedback inhibition was not compromised in n-3 deficient mice. Rather, glucocorticoid receptor (GR) signaling pathway was inactivated in the PFC but not in the hippocampus of n-3 deficient mice. Consequently, only dendritic arborisation in PFC was affected by dietary n-3 PUFAs deficiency. In addition, occlusion experiment with GR blockade altered GR signaling in the PFC of control mice, with no further alterations in n-3 deficient mice. In conclusion, n-3 PUFAs deficiency compromised PFC, leading to dendritic atrophy, but did not change hippocampal GR function and dendritic arborisation. We argue that this GR sensitivity contributes to n-3 PUFAs deficiency-related emotional behaviour deficits