Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA

Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer’s disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system, where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined

Interplay between n-3 and n-6 long-chain polyunsaturated fatty acids and the endocannabinoid system in brain protection and repair.

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFA) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) have shown beneficial effects on learning and memory, neuroinflammatory processes and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-archidonoylglycerol (2-AG) are the most widely studied endocannabinoids, and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) reverses corticosterone-induced changes in cortical neurons

Background: Chronic exposure to the glucocorticoid hormone corticosterone exerts cellular stress-induced toxic effects that have been associated with neurodegenerative and psychiatric disorders. Docosahexaenoic acid is a polyunsaturated fatty acid that has been shown to be of benefit in stress-related disorders, putatively through protective action in neurons. Methods: We investigated the protective effect of docosahexaenoic acid against glucocorticoid hormone corticosterone-induced cellular changes in cortical cell cultures containing both astrocytes and neurons. Results: We found that glucocorticoid hormone corticosterone (100, 150, 200 μM) at different time points (48 and 72 hours) induced a dose- and time-dependent reduction in cellular viability as assessed by methyl thiazolyl tetrazolium. Moreover, glucocorticoid hormone corticosterone (200 μM, 72 hours) decreased the percentage composition of neurons while increasing the percentage of astrocytes as assessed by βIII-tubulin and glial fibrillary acidic protein immunostaining, respectively. In contrast, docosahexaenoic acid treatment (6 μM) increased docosahexaenoic acid content and attenuated glucocorticoid hormone corticosterone (200 μM)-induced cell death (72 hours) in cortical cultures. This translates into a capacity for docosahexaenoic acid to prevent neuronal death as well as astrocyte overgrowth following chronic exposure to glucocorticoid hormone corticosterone. Furthermore, docosahexaenoic acid (6 μM) reversed glucocorticoid hormone corticosterone-induced neuronal apoptosis as assessed by terminal deoxynucleotidyl transferase–mediated nick-end labeling and attenuated glucocorticoid hormone corticosterone-induced reductions in brain derived neurotrophic factor mRNA expression in these cultures. Finally, docosahexaenoic acid inhibited glucocorticoid hormone corticosterone-induced downregulation of glucocorticoid receptor expression on βIII- tubulin-positive neurons. Conclusions: This work supports the view that docosahexaenoic acid may be beneficial in ameliorating stress-related cellular changes in the brain and may be of value in psychiatric disorders

Dietary Approaches and Supplements in the Prevention of Cognitive Decline and Alzheimer's Disease

Age-associated cognitive decline and dementia are conditions in which there is deterioration in memory, thinking, and behavior, with profound effects on the ability to perform everyday activities and well-being. Even if dementia mainly affects older persons, it is not a normal part of aging. Alzheimer's disease accounts for 60-75% of dementia cases. The number of persons affected will increase in the next decades in parallel with aging of the world population. Hence, unless some approach is found to reduce age-related deterioration of cognitive functions, health care costs will continue to rise exponentially. There is a wealth of epidemiological evidence supporting a relationship between diet and Alzheimer's disease, and suggesting that the risk of cognitive decline may be reduced by dietary interventions. It has been proposed that adopting a healthy diet and lifestyle that improves cardiovascular function may help delaying the onset of Alzheimer's disease due to its potential association with vascular disease. Several nutrients, dietary components, supplements and dietary patterns have been reported in relation to their association with cognition and with the development of cognitive decline and Alzheimer's disease. The possible effect of diet on the prevention of dementia is of tremendous scientific and general interest, because hitherto there is no definitive evidence of any effective pharmacological treatment for dementia. The aim of this review is to evaluate the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia

Effects of diet and/or exercise in enhancing spinal cord sensorimotor learning.

Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA:DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury

N-3 Polyunsaturated Fatty Acids and the Resolution of Neuroinflammation

In the past few decades, as a result of their anti-inflammatory properties, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), have gained greater importance in the regulation of inflammation, especially in the central nervous system (in this case known as neuroinflammation). If sustained, neuroinflammation is a common denominator of neurological disorders, including Alzheimer's disease and major depression, and of aging. Hence, limiting neuroinflammation is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 LC-PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators (SPMs) such as resolvins, maresins and protectins. These SPMs are crucially involved in the resolution of inflammation. They could be good candidates to resolve brain inflammation and to contribute to neuroprotective functions and could lead to novel therapeutics for brain inflammatory diseases. This review presents an overview 1) of brain n-3 LC-PUFAs as precursors of SPMs with an emphasis on the effect of n-3 PUFAs on neuroinflammation, 2) of the formation and action of SPMs in the brain and their biological roles, and the possible regulation of their synthesis by environmental factors such as inflammation and nutrition and, in particular, PUFA consumption

Alpha-linolenic omega-3 fatty acid for stroke protection: from brain preconditioning paradigm to nutrition

International audienceStroke is the third leading cause of death, due to its high incidence, theseverity of the insult, and lack of treatment options. The only therapeutic is restoration ofcerebral blood flow achieved by recombinant tissue plasminogen activator treatment,but only approximately 5% of patients receive it. In addition, therapeutics aimed atachieving neuroprotection by blocking the ischemic cascade, as identified in numerouspreclinical studies, failed in clinical trials. This failure in translation from experimentalmodels to clinical trials led to a re-evaluation of properties which would constitute the‘‘best-in class’’ therapeutics to be used against stroke. Given that neuroprotectionappears ineffective per se, an emerging direction is to identify therapies, probablycombinatorial in nature, which protect the whole neurovascular unit and target timedependentneurotoxic mechanisms. Molecules that activate complex cellular signalingcascades that render the brain resistant to subsequent ischemia, known aspreconditioners, offer a novel perspective in stroke protection. Preconditioning elicitscomplex endogenous neuroprotective responses that act by pleiotropic mechanisms toblock death pathways, promote survival pathways and increase resistance. In addition tochemical preconditioners, natural/endogenous compounds such as adenosine,glutamate, lysophospholipids, and omega-3 polyunsaturated fatty acids have beendemonstrated to be excellent preconditioners. Consequently, a major new concept inpreconditioning to combat stroke is introduced, which is preconditioning achievedthrough supplementation of an essential item in diet or as a nutraceutical. Severalepidemiologic studies suggested a beneficial effect of a seafood/omega-3-enriched dietin cerebral diseases, but the omega-3-induced protective mechanisms are still poorlyidentified. This review highlights how a-linolenic acid (ALA), the omega-3 polyunsaturatedfatty acid precursor, protects the brain from in vivo and in vitro models of stroke,thus potentially fulfilling the goal of identifying the ‘‘best-in class’’ therapeutics againststroke. Also described is the surprising pleiotric nature of ALA in protecting neurons,vasodilating brain arteries and stimulating neuroplasticity. Importantly, feasibility ofdelivery has been demonstrated, since ALA supplementation can be achieved throughmodification of the daily diet, for which prevention of stroke-induced mortality andcerebral damage has been confirmed. Therefore evaluating ALA as an interestingpreconditioner against stroke represents a novel and extremely relevant concept in thecontext of nutraceutical and functional food development