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n-3 Fatty Acids: Role in Neurogenesis and Neuroplasticity
Abstract
Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n-3 fatty acids, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and anti-apoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer's disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out.
... Numerous studies have demonstrated a connection between the consumption of n-3 polyunsaturated fatty acids (n-3 PUFA) in the diet and the occurrence of mental disorders [41][42][43]. Three n-3 PUFA, eicosapentaenoic acid (c5c8c11c14c17 C20:5, EPA), docosahexaenoic acid (c4c7c10c13c16c19 C22:6, DHA) and α-linolenic acid (c9c12c15 C18:3, ALA) have also been proven to improve cognitive function and mood through increased neurogenesis and synaptic protein expression [44]. Furthermore, a diet rich in DHA has been found to increase BDNF levels in the hippocampus, thereby enhancing cognitive function in rodent models of brain injury [45]. ...
Background/Objectives: Although physical activity and balanced diet may increase peripheral brain-derived neurotrophic factor (BDNF) concentration, little is known about whether these factors modify BDNF content in physically active individuals and whether the serum fatty acid (FA) profile is related. This study aimed to evaluate quality of diet, identify specific dietary patterns and assess their influence on BDNF and FA levels in serum. It is hypothesized that there is a correlation between diet quality and the concentrations of BDNF and FA in the serum of physically active male individuals. Methods: Physically active young adult male students at Jozef Pilsudski University of Physical Education in Warsaw (Poland) were enrolled. Dietary patterns were identified with cluster analysis and linear discriminant analysis (LDA) based on responses to a validated food frequency questionnaire, KomPAN® version 1.1. Results: Consumption of beverages, vegetables, milk, wholemeal bread/rolls, fruit and vegetable juices, butter, tinned vegetables and fruits were significant in the LDA model, in which three clusters were distinguished. Cluster 1 was characterized by more frequent consumption of wholemeal bread/rolls, milk, fruits, vegetables, fruit and vegetable juices and sweetened hot beverages and by significantly greater values for the pro-healthy diet index (p < 0.0001) and diet quality index (p < 0.0001) compared to Clusters 2 and 3. The diet of Cluster 2 was of the worst quality, as indicated by the higher values of the not-healthy diet index. Cluster 1 had the tendency for the highest BDNF levels (of the best quality of diet), and a tendency for decreased BDNF concentration with an increased physical activity level was observed. Conclusions: Physical activity, diet quality and BDNF level depend, correlate and interact with each other to provide both optimal physical and mental health.
... These critical fatty acids are concentrated at high levels in the brain, where they affect cognitive, social, and linguistic capabilities, as well as fundamental growth and development processes. A lack of alpha-linolenic acid and its omega-3 derivatives has been linked to behavioral changes, eyesight impairment, tingling in the limbs and extremities, loss of motor coordination, and growth retardation, according to previous research [14][15][16][17]. ...
Objectives
Valosin-containing protein (p97/VCP) and its cofactor, small p97/VCP-interacting protein (SVIP), are involved in the endoplasmic reticulum - associated degradation pathway (ERAD). We investigated the cellular localization of vitamin D receptor (VDR), ERAD, and autophagic proteins (LC3B and p62) in rat brain tissue.
Methods
There were four groups consisting of 24 Wistar albino rats: control and treatment groups for vitamin D, omega-3, and both vitamin D and omega-3. Brain tissues were stained with hematoxylin-eosin, azan trichrome, and toluidine blue for histopathological evaluation. The immunohistochemistry assay was performed for VDR, p97/VCP, SVIP, LC3B, and p62 in rat brain sections.
Results
The immunoexpression of VDR and p97/VCP was significantly increased in hippocampus and cortex of brain tissue from the vitamin D-supplemented group. Furthermore, the protein expression level of SVIP reached the highest level in vitamin D-treated group. LC3B and p62 revealed reduced expressions in vitamin D-treated group in rat brain and hippocampus, in contrast to p97/VCP, SVIP, and VDR.
Conclusions
Vitamin D and omega-3 supplementations had no negative effects at a cellular level on hippocampus and cortex of the brain tissue. Vitamin D increased the expression of the proteins that are related to the ERAD pathway, whereas it reduced the expression of the proteins in the autophagy pathway. Also, in this study, SVIP expressions were shown in rat hippocampus and cortex of the brain tissue.
... A scientific explanation for their function is that PUFAs omega-3 (ALA, EPA, and DHA) enhance neurogenesis in the adult hippocampus, promote synaptic plasticity, and modulate synaptic protein expression. This allows PUFAs, especially ALA, to be used as a therapeutic for neurode-generative diseases [65]. The cognitive function of 60 healthy elderly subjects with an average age of 72 years was tested after using a diet enriched with 2.2 g ALA [66]. ...
The present review investigates the relationship between polyunsaturated fatty acids (PUFAs) and mental health disorders, such as dementia, psychosis, schizophrenia, Alzheimer’s disease, anorexia nervosa, and impairment problems in animals and human models. Data were collected from a variety of studies: randomized intervention trials, observational and interventional studies, case reports, and epidemiological studies. The evidence suggests that PUFAs are beneficial for mental health, brain function, and behavior. ALA, EPA, and DHA have very significant neuroprotective properties, particularly in inducing changes to the synaptic membrane and modulating brain cell signaling. In the case of neurodegenerative disorders, PUFAs incorporated into cellular membranes have been shown to protect against cell atrophy and death. The formal analyses of the included studies pointed to a decrease in ALA, EPA, and DHA levels in various populations (e.g., children, adolescents, adults, and seniors) presenting with different types of mental disorders. These results indicate that PUFA supplementation may be considered as an innovative therapeutic strategy to reduce the risk of neuronal degeneration.
Atopic dermatitis (AD) is a chronic inflammatory skin disease with multifactorial and unclear pathogenesis. Its development is characterized by two key elements: epigenetic dysregulation of molecular pathways involved in AD pathogenesis and disrupted skin and gut microbiota (dysbiosis) that jointly trigger and maintain chronic inflammation, a core AD characteristic. Current data suggest that failed inflammation resolution is the main pathogenic mechanism underlying AD development. Inflammation resolution is provided by specialized pro-resolving mediators (SPMs) derived from dietary polyunsaturated fatty acids acting through cognate receptors. SPM levels are reduced in AD patients. Administration of SPMs or their stable, small-molecule mimetics and receptor agonists, as well as supplementation with probiotics/prebiotics, demonstrate beneficial effects in AD animal models. Epidrugs, compounds capable of restoring disrupted epigenetic mechanisms associated with the disease, improve impaired skin barrier function in AD models. Based on these findings, we propose a novel, multilevel AD treatment strategy aimed at resolving chronic inflammation by application of SPM mimetics and receptor agonists, probiotics/prebiotics, and epi-drugs. This approach can be used in conjunction with current AD therapy, resulting in AD alleviation.
The brain relies on a range of nutrients for optimal functioning. However, the causal nature between dietary components and human intelligence are still unclear. This study integrates Mendelian randomization (MR) and genome-wide associations analyses to investigate the relationships. The results show that cheese exerts the most remarkable genetic correlation and causal association with cognition-related traits. We conduct a large-scale meta-analysis of genome-wide associations studies (GWAS) consisting of over 800,000 participants and discover 71 genetic determinants for cheese consumption. Additional MR using the GWAS results recovers the causal effects of cheese on all the cognition-related traits, and also reveals its effects on education, psychological states and gene expressions in multiple brain tissues. Additionally, knockout mouse models and pathway enrichment analysis indicate that the loci mapped genes are involved in cognitive functions and brain characteristics. In conclusion, our comprehensive analysis supports the potential benefits of cheese consumption on human intelligence.
Polyunsaturated fatty acids (PUFAs) are critical to nervous system function and structure, but their rates of incorporation from plasma into brain have not been evaluated. In the adult rat, calculations based on our model show that at least 3–5% of esterified brain arachidonic acid (AA) and 2–8% of esterified brain docosahexaenoic acid (DHA) are replaced daily by unesterified PUFAs in plasma. These rates, when related to unlabeled brain PUFA composition, give half-lives of 1–2 weeks for plasma-brain exchange of AA and DHA. In the human brain, the arachidonate replacement rate is 0.3% per day.
Although unesterified plasma PUFA concentrations are low, their rates of incorporation into brain are sufficient to compensate for metabolic and efflux losses, so that PUFA transport from plasma into brain as a component of a lipoprotein is unnecessary. Dietary supplementation, by altering plasma unesterified PUFA concentrations, can regulate brain PUFA content and may help to treat brain diseases involving PUFA imbalance.
Adipose differentiation is regulated by coordination of several signaling pathways and transcription factors. We recently showed that Hypoxia inducible factor-2α (HIF-2α) plays several supporting roles in adipose differentiation and adipocytes functions including regulation of glucose uptake followed by lipid synthesis. HIF-2α expression is increased during adipogenesis, indicating that its up-regulation is necessary for execution of adipogenesis and maintenance of mature adipocytes functions. Therefore, in this study, to understand the mechanism by which HIF-2α expression is induced during adipogenesis, we investigated the promoter activity of HIF-2α gene during adipogenesis in 3T3-L1 cells. A comparison of HIF-2α promoter activity between preadipocytes and adipocytes revealed that the sequence -478/-445 is the putative core element that contributes to differentiation- dependent up-regulation of HIF-2α promoter activity. Electrophoretic mobility shift assays showed the presence of the specific nuclear factor bound to the sequence -478/-445 in both preadipocytes and adipocytes. Computer analysis revealed that this element contains several Sp1/Sp3 binding sites. Indeed, the presence of Sp1/Sp3 consensus oligonucleotides diminished the formation of the complexes composed of the sequence -478/-445 and the nuclear factor. Furthermore, specific retarded bands were supershifted with anti-Sp1 or -Sp3 antibodies. Binding of Sp1 and Sp3 to this element was also confirmed by chromatin immunoprecipitation analysis. The element encompassing -478/-445 favors Sp3 in preadipocytes and Sp1 in adipocytes. Finally, the activity of -478/-445 was increased by Sp1 but decreased by Sp3. Consequently, these results suggest that Sp1 and Sp3 are involved in transcriptional regulation of HIF-2α expression during adipogenesis in 3T3-L1 cells.
Background
ω3 Fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether ω3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder.
Methods
A 4-month, double-blind, placebo-controlled study, comparing ω3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder.
Results
A Kaplan-Meier survival analysis of the cohort found that the ω3 fatty acid patient group had a significantly longer period of remission than the placebo group (P=.002; Mantel-Cox). In addition, for nearly every other outcome measure, the ω3 fatty acid group performed better than the placebo group.
Conclusion
ω3 Fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.
This study examined the associations between a high-K fitness strategy (i.e., a Darwinian reproductive strategy where the individual invests significantly in a smaller number of offspring) and PTSD on a sample of 1400 disaster workers who had exposure to a singular traumatic event (the 9/11 attack on the World Trade Center in New York City). The participants underwent psychological evaluations consisting of 1) Clinician-Administered PTSD Scale (CAPS) and 2) PTSD Checklist (PCL).The participants were also administered the 3) High-K Strategy Scale (HKSS) (Giosan, 2006). Other factors, such as demographics, prior trauma, prior psychiatric history, and the severity of exposure to 9/11 were also captured. The results showed that HKSS score was an important negative predictor of PTSD, accounting for 10% of the variance in the PCL and 5% of the variance in the CAPS, after controlling for demographics, prior trauma, prior psychiatric history and the severity of exposure to 9/11. The findings speak against the evolutionary view that PTSD symptoms are adaptive while strengthening the evolutionary view that PTSD is the expression of an overlearned survival response in vulnerable individuals (Silove, 1998), which, when activated, can have significant negative effects on fitness.
Dietary omega-3 polyunsaturated fatty acids (ω-3 PUFA) reduce sunburn, an acute inflammatory response, in humans. We assessed whether this may be mediated by reduced ultraviolet-B (UV-B) induction of proinflammatory mediators tumor necrosis factor–α (TNF-α), interleukin (IL)-1β, IL-6, IL-8 and prostaglandin (PG)E2 in healthy skin. In a double-blind, randomized study, 28 humans received 4 g daily of 95% ethyl esters of eicosapentaenoic acid (EPA) or oleic acid (OA) orally for 3 months. Skin biopsies and suction blister fluid were taken from unexposed and UV-B–exposed skin and examined for mediator expression immunohistochemically and quantitatively by immunoassay; plasma levels were also assayed. The subjects taking EPA, but not OA, showed a significant rise in their minimal erythemal dose (MED) (data reported elsewhere). Before supplementation, irradiation with 3× MED UV-B increased blister fluid TNF-α, IL-6, IL-8 and PGE2 at 16 h (all P < 0.001). No significant change occurred in baseline or UV-B–induced skin levels of cytokines after either supplement, whereas UV-B induction of PGE2 was abolished after EPA but not OA. Immunohistochemical expression of the cytokines at baseline and after UV-B was unaltered by EPA and OA; circulating cytokine and PGE2 levels were also unchanged. Hence, in healthy skin in vivo, there was no evidence that reduction of the sunburn response by EPA is mediated by the proinflammatory cytokines examined; abrogation of UV-B–generated PGE2 may play a role.