Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

Dietary polyunsaturated fatty acids (PUFAs) have gained more importance these last decades since they regulate the level of long-chain PUFAs (LC-PUFAs) in all cells and especially in brain cells. Because LC-PUFAs, especially those of the n-3 family, display both anti-inflammatory and pro-resolution properties, they play an essential role in neuroinflammation. Neuroinflammation is a hallmark of neurological disorders and requires to be tightly controlled or at least limited otherwise it can have functional consequences and negatively impact the quality of life and well-being of patients. LC-PUFAs exert these beneficial properties in part through the synthesis of specialized pro-resolving mediators (SPMs) that are involved in the resolution of inflammation and to the return of homeostasis. SPMs are promising relevant candidates to resolve brain inflammation and to contribute to neuroprotective functions and lead to novel therapeutics for brain inflammatory diseases. Here we present an overview of the origin and accumulation of PUFAs in the brain and brain cells and their conversion into SPMs that are involved in neuroinflammation and how nutrition induces variations in LC-PUFA and SPM levels in the brain and in brain cells

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

Differential effect of maternal diet supplementation with α-Linolenic adcid or n-3 long-chain polyunsaturated fatty acids on glial cell phosphatidylethanolamine and phosphatidylserine fatty acid profile in neonate rat brains

<p>Abstract</p> <p>Background</p> <p>Dietary long-chain polyunsaturated fatty acids (LC-PUFA) are of crucial importance for the development of neural tissues. The aim of this study was to evaluate the impact of a dietary supplementation in n-3 fatty acids in female rats during gestation and lactation on fatty acid pattern in brain glial cells phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the neonates.</p> <p>Methods</p> <p>Sprague-Dawley rats were fed during the whole gestation and lactation period with a diet containing either docosahexaenoic acid (DHA, 0.55%) and eicosapentaenoic acid (EPA, 0.75% of total fatty acids) or α-linolenic acid (ALA, 2.90%). At two weeks of age, gastric content and brain glial cell PE and PS of rat neonates were analyzed for their fatty acid and dimethylacetal (DMA) profile. Data were analyzed by bivariate and multivariate statistics.</p> <p>Results</p> <p>In the neonates from the group fed with n-3 LC-PUFA, the DHA level in gastric content (+65%, P < 0.0001) and brain glial cell PE (+18%, P = 0.0001) and PS (+15%, P = 0.0009) were significantly increased compared to the ALA group. The filtered correlation analysis (P < 0.05) underlined that levels of dihomo-γ-linolenic acid (DGLA), DHA and n-3 docosapentaenoic acid (DPA) were negatively correlated with arachidonic acid (ARA) and n-6 DPA in PE of brain glial cells. No significant correlation between n-3 and n-6 LC-PUFA were found in the PS dataset. DMA level in PE was negatively correlated with n-6 DPA. DMA were found to occur in brain glial cell PS fraction; in this class DMA level was correlated negatively with DHA and positively with ARA.</p> <p>Conclusion</p> <p>The present study confirms that early supplementation of maternal diet with n-3 fatty acids supplied as LC-PUFA is more efficient in increasing n-3 in brain glial cell PE and PS in the neonate than ALA. Negative correlation between n-6 DPA, a conventional marker of DHA deficiency, and DMA in PE suggests n-6 DPA that potentially be considered as a marker of tissue ethanolamine plasmalogen status. The combination of multivariate and bivariate statistics allowed to underline that the accretion pattern of n-3 LC-PUFA in PE and PS differ.</p

Short-Term Long Chain Omega3 Diet Protects from Neuroinflammatory Processes and Memory Impairment in Aged Mice

Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects

Primary open-angle glaucoma: association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and plasma 24-hydroxycholesterol levels

Purpose. Genetics has made significant contributions to the study of glaucoma over the past few decades. Cholesterol-24S-hydroxylase (CYP46A1) is a cholesterol-metabolizing enzyme that is especially expressed in retinal ganglion cells. CYP46A1 and its metabolic product, 24S-hydroxycholesterol, have been linked to neurodegeneration. A single-nucleotide polymorphism (SNP) in the CYP46A1 gene, designated as rs754203 and associated with Alzheimer disease, was evaluated as a genetic risk factor for primary open-angle glaucoma (POAG), as well as plasma 24S-hydroxycholesterol levels. Methods. The frequency of the CYP46*C and CYP46*T alleles was analyzed in 150 patients with POAG and 118 control subjects. Plasma 24S-hydroxycholesterol levels were quantified. Sex, age, alleles, and genotype frequencies between patients with POAG and control subjects were compared by using the {chi}2 and Student's t-tests. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression to assess the relative association between disease and age, sex, and genotypes. Results. The frequency of the TT genotype was significantly higher in patients with POAG than in control subjects (61.3% versus 48.3%, respectively, OR = 1.26; 95% CI = 1.006–1.574, P < 0.05). Plasma 24S-hydroxycholesterol levels did not differ between control subjects and patients with POAG. The ratio of estimated brain weight to liver volume as an estimate of the capacity of the human body to synthesize and metabolize 24S-hydroxycholesterol was found to correlate to plasma 24S-hydroxycholesterol in control subjects and patients with POAG. Conclusions. The rs754203 SNP in CYP46A1 was associated with a risk for POAG. This polymorphism was not associated with changes in plasma 24S-hydroxycholesterol, highlighting that despite its retinal origin, 24S-hydroxycholesterol cannot be used as a biomarker for POAG

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

Chronic supplementation with a mix of salvia officinalis and salvia lavandulaefolia improves morris water maze learning in normal adult C57Bl/6J mice

Background: Two different species of sage, Salvia officinalis and Salvia lavandulaefolia, have demonstrated activities in cognitive function during preclinical and clinical studies related to impaired health situations or single administration. Different memory processes have been described to be significantly and positively impacted. Objective: Our objective is to explore the potential of these Salvia, and their additional activities, in healthy situations, and during prolonged administration, on memory and subsequent mechanisms of action related to putative effects. Design: This mouse study has implicated four investigational arms dedicated to control, Salvia officinalis aqueous extract, Salvia lavandulaefolia-encapsulated essential oil and a mix thereof (Cognivia™) for 2 weeks of administration. Cognitive functions have been assessed throughout Y-maze and Morris water maze models. The impact of supplementation on lipid peroxidation, oxidative stress, neurogenesis, neuronal activity, neurotrophins, neurotrophin receptors, CaM kinase II and glucocorticoid receptors has been assessed via post-interventional tissue collection. Results: All Salvia groups had a significant effect on Y-maze markers on day 1 of administration. Only the mix of two Salvia species demonstrated significant improvements in Morris water maze markers at the end of administration. Considering all biological and histological markers, we did not observe any significant effect of S. officinalis, S. lavandulaefolia and a mix of Salvia supplementation on lipid peroxidation, oxidative stress and neuronal plasticity (neurogenesis, neuronal activity, neurotrophins). Interestingly, CaM kinase II protein expression is significantly increased in animals supplemented with Salvia. Conclusion: The activities of Salvia alone after one intake have been confirmed; however, a particular combination of different types of Salvia have been shown to improve memory and present specific synergistic effects after chronic administration in healthy mice

Supplementation with low molecular weight peptides from fish protein hydrolysate reduces acute mild stress-induced corticosterone secretion and modulates stress responsive gene expression in mice

First evidence started to demonstrate the anxiolytic effects of low molecular weight peptides extracted from natural products, such as fish hydrolysate, but their underlying mechanisms remain to be elucidated. The objective of this study was to evaluate the effect of a chronic administration of fish hydrolysate on stress reactivity and to understand the mechanisms involved. Stress response (corticosterone secretion, expression of stress-responsive genes) was measured in Balb/c mice supplemented with fish hydrolysate (300 mg/kg body weight) or vehicle daily for 7 days before being submitted to an acute mild stress protocol. Our results demonstrated that 30 min after stress induction, fish hydrolysate decreased corticosterone level compared to control mice. Moreover, fish hydrolysate supplementation modulated expression of stress responsive genes involved in hypothalamic pituitary adrenal axis regulation, circadian rhythm and aging process. These findings suggest that fish hydrolysate represents an innovative strategy to prevent stress-induced aversive effects and participate in stress management

Fish Hydrolysate Supplementation Containing n-3 Long Chain Polyunsaturated Fatty Acids and Peptides Prevents LPS-Induced Neuroinflammation

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1β (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation