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Long-chain omega-3 fatty acids and the brain: A review of the independent
and shared effects of EPA, DPA and DHA
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Dyall SC (2015) Long-chain omega-3
fatty acids and the brain: a review of
Introduction
the independent and shared effects
of EPA, DPA and DHA.
There is mounting evidence supporting the beneficial effects of an increased intake of omega-3
Front. Aging Neurosci. 7:52. polyunsaturated fatty acids (PUFAs) in a variety of neurodegenerative and neurological conditions
doi: 10.3389/fnagi.2015.00052 (Dyall and Michael-Titus, 2008; Dyall, 2010; Denis et al., 2015). However, comparing results
between studies has traditionally been hampered by a lack of 2012), and also in diseases such as cancer, insulin resistance, and
discrimination between the different omega-3 PUFAs and results cardiovascular disease (Anderson and Ma, 2009; Mozaffarian
are typically attributed the omega-3 PUFAs as a whole (Dyall, and Wu, 2012). The aim of this current article is to review the
2011). There is accumulating evidence that certain effects may be effects of the different long-chain omega-3 PUFAs in the brain
unique and specific to individual omega-3 PUFAs and there can in normal aging and neurodegenerative disorders. Although the
no longer be an assumption of equivalence in either mechanism short-chain omega-3 PUFAs, α-linolenic acid (ALA, 18:3n-3)
of action or function. This issue is particularly important when and stearidonic acid (SDA, 18:4n-3) have shown potential health
pooling studies in systematic reviews and meta-analyses. For benefits (Barceló-Coblijn and Murphy, 2009; Whelan, 2009),
example, two recent meta-analyses into the effects of EPA these have yet to be sufficiently explored in the context of central
and DHA in depression reviewed predominantly the same nervous system (CNS) disorders, and therefore this review will
studies, but produced substantially different outcomes (Sublette be restricted to EPA, DPA and DHA.
et al., 2011; Bloch and Hannestad, 2012). Bloch and Hannestad
found only small, non-significant benefits, with no significant EPA, DPA and DHA Metabolism
differences between EPA and DHA (Bloch and Hannestad,
2012). Whereas Sublette and coworkers used a mixed-effect The omega-3 PUFA series begins with ALA with the other
model, separating the treatments by EPA content, and found omega-3 PUFAs derived from ALA via a series of desaturation,
that only supplements with the proportion of EPA ≥ 60% of the elongation and ultimately β-oxidation reactions (Moore et al.,
total EPA and DHA content in a dose range of 200–2200 mg 1995; Gregory et al., 2011), summarized in Figure 1. The pathway
EPA in excess of DHA effective against primary depression begins with the desaturation of ALA to SDA by ∆6 desaturase
(Sublette et al., 2011). Although a number of methodological (encoded by FADS2 genes), which is a rate limiting step. This
differences between the meta-analyses may have contributed is followed by elongation (ELOVL1 gene) to eicocosatetraenoic
to the different outcomes (Lin et al., 2012b); this incongruity acid (20:4n-3). Desaturation by ∆5 desaturase (FADS1 gene)
between findings highlights the importance of considering the produces EPA and EPA is then elongated by elongase-2
omega-3 PUFAs as biologically distinct molecules. Furthermore, (ELOVL2 gene) first to DPA and then tetracosapentaenoic acid
although current evidence suggests that EPA and DHA are the (24:5n-3). Tetracosapentaenoic acid then undergoes a second ∆6
predominant biological omega-3 PUFAs, the bioactive effects of desaturation to produce tetracosahexaenoic acid (24:6n-3). These
docosapentaenoic acid (DPA, 22:5n-3) are gaining recognition in initial steps occur in the endoplasmic reticulum; however, the
the literature (Kaur et al., 2011). final stage of DHA synthesis occurs in the peroxisome following
A number of excellent reviews have discussed the translocation. In the peroxisome 24:6n-3 is shortened to DHA
complementary and divergent effects of the different omega-3 (22:6n-3) by a single round of β-oxidation by the action of
PUFAs both at the fundamental level in terms of cell signaling acyl-coenzyme-A oxidase (ACOX1 gene), D -bifunctional enzyme
and function (Gorjão et al., 2009; Russell and Bürgin-Maunder, (HSD1784 gene) and then peroxisomal thiolases.
FIGURE 1 | Synthesis of EPA, DPA and DHA from ALA. The longer tetracosahexaenoic acid (24:6n-3) is translocated to the peroxisome and is
chain omega-3 polyunsaturated fatty acids (PUFAs) are synthesized from shorted by one cycle of the β-oxidation pathway to form DHA (22:6n-3).
ALA by a progressive series of enzymatic desaturation and chain For further details refer to the text. Figure adapted from Dyall and
elongation steps, initially in the endoplasmic reticulum. In the final stage Michael-Titus (2008).
Metabolism
Sprague Dawley rats DPA increased DPA in all tissues and DHA in the liver. DPA also partly retro-converted to EPA in liver, adipose Kaur et al. (2010)
tissue, heart and skeletal muscle.
Sprague Dawley rats DPA increased DPA in heart and liver and increased EPA content with the retro-conversion particularly Holub et al. (2011)
pronounced in the kidney.
Wistar rats DPA and DHA β-oxidized significantly less than EPA at 6 h, and higher incorporation of DPA and DHA in Kaur et al. (2013)
skeletal muscle and heart than EPA.
Sprague Dawley rats Greater excretion of DPA in feces than EPA. EPA and DPA similarly increased EPA, DPA and total long chain Ghasemi Fard et al. (2014)
omega-3 PUFAs in the liver.
Healthy females After 4 days supplementation DPA increased EPA, DPA and DHA content of plasma or RBC lipids, whereas Miller et al. (2013)
(age 21–30 years) EPA only increased EPA content.
Healthy females EPA and DPA metabolized differently postprandially. DPA significantly decreased chylomicronemia compared Linderborg et al. (2013)
(age 20–30 years) to EPA.
Neuroprotection
Young (3–4 months) EPA increased cortical tissue DPA and DHA in young and old rats and EPA in old rats, whereas DPA Kelly et al. (2011)
and old (20–22 months) increased DPA in young and old rats and DHA in young rats. EPA and DPA similarly down-regulated age-
rats related microglial activation, decreased activation of sphingomyelinase and caspase 3 and restored long-term
potentiation and improved spatial memory in the aged rats.
Inflammation
Mice neutrophils and DPA-derived PD1n-3 DPA significantly reduced neutrophil recruitment during peritonitis of mice and stimulated Aursnes et al. (2014)
human macrophages macrophage phagocytosis and clearance of apoptotic human neutrophils, both to a similar extent to DHA-
derived PD1.
Human macrophages DPA-derived Mar1n-3 DPA stimulated macrophage phagocytosis and clearance of apoptotic human Tungen et al. (2014)
neutrophils to a similar extent to that of DHA-derived Mar1.
* For a detailed review of the metabolism and biological effects of DPA prior to 2011 see Kaur et al. (2011).
Although this pathway is now well characterized, the in Table 1, where it appears a potential role for DPA may be to
efficiency and kinetics of conversion in humans has been act as a reservoir for EPA and DHA. Earlier studies have been
somewhat harder to establish. There are limited tissues readily extensively reviewed by Kaur et al. (2011).
available for analysis, so blood components are typically It has also been demonstrated that variations in genes
analyzed, which although showing strong correlations with involved in the biosynthesis and metabolism of omega-3 PUFAs
peripheral tissues, may not reflect the composition of the CNS affects their blood levels. In a study of 8866 participants from
(Tu et al., 2013). Furthermore, it has long been known that European ancestry single nucleotide polymorphisms (SNPs)
blood components differ in their metabolism and incorporation in desaturase genes FADS1 (∆5 desaturase) and FADS2 (∆6
of EPA, DPA and DHA (Brown et al., 1991). In an early short- desaturase) were associated with higher ALA and lower EPA
term fish oil supplementation study erythrocyte EPA was a and DPA plasma phospholipid levels, suggesting different rates
stronger indicator of omega-3 PUFA intake than DPA or DHA, of conversion (Lemaitre et al., 2011). Similarly, higher levels
potentially due to differential incorporation into the membrane of EPA and DPA and lower DHA were associated with SNPs
phospholipids. EPA content appears to be largely determined in ELOVL2 (elongase 2). Furthermore, those with the apoE-
by exchange with plasma lipoproteins, whereas DPA and DHA ε4 (ApoE-ε4) polymorphism show a lower response to EPA
are more enriched in the inner membrane and are therefore and DHA supplementation (Plourde et al., 2009), and disturbed
more influenced by erythrocyte turnover (Brown et al., 1991). DHA metabolism, such that DHA has a significantly decreased
More recently these different incorporation rates and efficiencies half-life and enhanced β-oxidation (Chouinard-Watkins et al.,
have also been shown in other blood components (Metherel 2013). The ApoE-ε4 allele is the major genetic risk factor for
et al., 2009; Miller et al., 2013). For example, when participants the development of late onset AD (Hauser and Ryan, 2013), and
were given 8 g of pure EPA or DPA over a 7 day period, EPA importantly ApoE-ε4 carriers seem not to be protected against
supplementation significantly increased EPA in erythrocytes and AD when consuming fish (Chouinard-Watkins et al., 2013).
plasma cholesterol esters and phospholipids, but not plasma Gender also appears to differentially affect long-chain omega-3
triacylglycerols. Whereas, DPA supplementation significantly PUFA levels, whereby females have significantly lower blood
increased DPA in plasma triacylglycerols and phospholipid levels of DPA and EPA, but significantly higher DHA than males
fractions, but not erythrocyte or plasma cholesterol esters (Miller (Metherel et al., 2009).
et al., 2013). These differential efficiencies of incorporation are These individual variations in response also extend to
not be restricted to blood and are also seen in adipose tissue changes in the levels of omega-6 and omega-3 PUFA-derived
(Katan et al., 1997). Recent studies investigating the differences metabolites (Nording et al., 2013). In this detailed lipidomics
in metabolism between EPA, DPA and DHA are summarized analysis 12 subjects were given 1.9 g/day EPA and 1.5 g/day
DHA for 6 weeks. There were some shared responses to the It is currently unclear why brain phospholipids are specifically
supplementation with the participants, such as significantly enriched in DHA and low in DPA and EPA. As described
decreased plasma triacylglycerols, very low density lipoproteins above, biosynthesis of DHA from DPA involves elongation
(VLDLs) and chylomicron particles. However, there was also a and desaturation, followed by translocation to the peroxisome
very high degree of inter-individual variability in the effects of for β-oxidation. This is not only more energetically costly,
supplementation on the production of omega-6 and omega-3 but also introduces PUFAs into the membrane with much
PUFA-derived metabolites. For example, production of the EPA greater potential for peroxidation. Furthermore, this specific
lipoxygenase (LOX) metabolite 12-hydroxyeicosapentaenoic DHA enrichment is conserved across species (Crawford et al.,
acid (12-HEPE) varied between subjects from an 82% decrease 1976; Farkas et al., 2000), suggesting that there a highly specific
to a 5,000% increase. requirement for DHA in the neuronal membrane.
However, in spite of these individual variations, studies
into the effects of omega-3 PUFA supplementation on blood Effects of EPA, DPA and DHA on Neuronal
composition in normal healthy adults consuming Western diets Membrane Properties
do show some consistent responses (Arterburn et al., 2006;
Brenna et al., 2009). ALA supplementation induces significant A variety of membrane effects have been shown with DHA,
increases in EPA and DPA content, but has negligible effects including modulating key biophysical properties such as acyl
on DHA content in plasma or blood cells (in the order of 1% chain order, membrane fluidity, phase behavior, compression,
in infants and much lower in adults). EPA supplementation permeability, fusion, flip-flop and protein activity (Stillwell
increases blood EPA and DPA levels to an approximately and Wassall, 2003; Stillwell et al., 2005), and driving the
15-fold greater extent than ALA, but also does not affect DHA. creation of cholesterol-depleted domains (Wassall and Stillwell,
Only pre-formed DHA supplementation significantly increases 2008). However, there have been few direct comparisons of
blood DHA levels (Brenna et al., 2009). Consequently the most the membrane properties of EPA, DPA and DHA, to explain
consistent way to increase EPA, DPA or DHA blood content is to this indispensable role, although recently DHA and EPA were
supplement with that particular PUFA. However, care does needs shown to partition differently in raft and non-raft domains
to be taken when comparing between studies and extrapolating in membranes (Williams et al., 2012). DHA had a much
from blood to CNS levels. greater tendency to accumulate into sphingomyelin/cholesterol-
rich lipid rafts than EPA, and therefore had a much greater
EPA, DPA and DHA Metabolism in the Brain potential to affect cell signaling by modify the composition of
these lipid rafts. A further intriguing recent hypothesis for the
The brain has a unique fatty acid composition with high indispensable nature of DHA suggests that the unique structure
levels of palmitate (16:0), the omega-6 PUFA arachidonic acid of DHA allows for the quantum transfer and communication of
(AA, 20:4n-6), and DHA, but low levels of other omega-3 π-electrons across the membrane (Crawford et al., 2013). This
PUFAs, especially EPA (Crawford et al., 1976; Brenna and hypothesis offers an explanation for the precise depolarisation of
Diau, 2007). Indeed, brain EPA levels are typically 250–300 retinal membranes and the cohesive, organized neural signaling
times lower than DHA (Chen et al., 2009). Thus, DHA essential for higher intelligence.
is quantitatively the most important omega-3 PUFA in the An important role for DHA in the membrane is to modulate
brain. In addition to differences in tissue levels of EPA, DPA the synthesis of PS, as the accumulation and biosynthesis of PS
and DHA, there are also differences in their phospholipid in neuronal tissues is sensitive to the level of membrane DHA
location within the brain, such that DHA and DPA are (Garcia et al., 1998) and 18:0, DHA is the most abundant PS
predominantly enriched in phosphatidylethanolamine (PE) species in the brain (Kim et al., 2014a). The biosynthesis of PS
and phosphatidylserine (PS), whereas EPA appears preferably occurs from pre-existing phosphatidylcholine (PC) or PE via
esterified to phosphatidylinositol (PI; Chen et al., 2009). Indeed, serine base exchange, and DHA at the sn-2 position on PC is
EPA shares this proclivity for PI with the AA, which is also highly more favorably converted to PS (Kim et al., 2004). Increasing
enriched in PI (Lee and Hajra, 1991), and may be related to their the PS content of neuronal membranes may positively affect
equivalent chain length. neuronal survival via the PI 3-kinase/Akt signaling pathway
The endogenous synthesis of EPA, DPA and DHA are (Akbar et al., 2005). However, when directly compared, dietary
low within the brain compared with uptake from the plasma EPA and DHA similarly increase brain phospholipid levels
unesterified fatty acid pool (Demar et al., 2005, 2006), suggesting (Cansev and Wurtman, 2007). Gerbils fed EPA or DHA (300
that the brain maintains levels via the uptake from dietary and/or mg/kg/day by oral gavage) had significantly increased brain
liver sources in plasma. Using an in situ cerebral perfusion levels of PE, PS and PI compared to animals on the control
competition assay, EPA and DHA were found to enter the diet. The DHA group also had significantly increased PC levels.
brain at similar rates, and therefore appear to cross the blood These effects were accompanied by increases in the levels of pre
brain barrier by simple diffusion (Ouellet et al., 2009), and and post-synaptic proteins, syntaxin-3, PSD-95 and synapsin-1,
presumably DPA acts in the same manner. The low levels and were not seen with following AA treatment. In addition
of EPA are maintained by multiple mechanisms including to the accumulation of phospholipids DHA has further effects
β-oxidation, decreased incorporation, elongation to DPA and on membrane phospholipid composition. A detailed lipidomics
lower phospholipid recycling (Chen et al., 2013; Kaur et al., 2013). analysis found that rats supplemented with 10 mg/day of
DHA for 8 weeks induced multiple changes in phospholipid which is further metabolized to other prostaglandin series (PG),
composition, including the production of new PS and PI species prostacyclins (PGI), thromboxanes (TXA), LT, lipoxins (LX),
(Little et al., 2007). hydroxy and hydroperoxy fatty acids (Smith et al., 2000).
The indispensable nature of DHA in neuronal membranes has Vertebrates have two principal isoforms of COX: COX-1 and
also been shown by omega-3 PUFA dietary deficiency studies, COX-2 (Kulmacz et al., 2003).
whereby reduction of brain phospholipid DHA consistently In most tissues COX-1 is constitutively expressed, whereas
produces reciprocal increases in the levels of DPAn-6 (Enslen COX-2 is inducible. However, in specialized cell types such
et al., 1991; Contreras et al., 2001). Since omega-3 and as the neurones in the CNS, constitutive COX-2 expression is
omega-6 PUFAs are recycled independently of each other, this observed in the cortex and allocortical structures, such as the
relationship is probably maintained through competition for hippocampus and amygdala (Breder et al., 1995). COX-2 is
∆6D (Contreras et al., 2001). Omega-3 PUFAs competitively particularly enriched in the hippocampus and cortex (Yamagata
inhibit the desaturation of linoleic acid (18:2n-6) by ∆6D et al., 1993), where expression is localized in the postsynaptic
(Galli et al., 1971), and therefore subsequent biosynthesis of dendritic spines (Kaufmann et al., 1996), suggesting a role in
longer chain omega-6 PUFAs. This reciprocal relationship neural activity and activity-dependent plasticity. COX-1 and -2
maintains the degree of phospholipid membrane unsaturation to have similar structures, although COX-1 has a smaller active site
approximately constant levels, in a process called ‘‘homeoviscous (Rowlinson et al., 2000). This size restriction imposes a substrate
compensation’’ (Garda et al., 1994). However, in spite of this specificity on COX-1 for C20 fatty acids (Kulmacz et al., 2003),
homeoviscous compensation profound and widespread effects and is unable to oxygenate DHA (Corey et al., 1983). The COX-2
are observed when tissue DHA levels are decreased, such active site is about 20% larger (Smith et al., 2000) and this enzyme
as alterations to membrane properties (Eldho et al., 2003), is consequently able to metabolize a larger range of substrates,
decreases in performance in tasks of spatial memory (Lim with differing acyl chain length and degree of unsaturation,
et al., 2005), altered enzyme activity and electrophysiological potentially including DPA and DHA.
properties (Bourre et al., 1989), and altered neurotransmission The SPMs are a rapidly expanding class of autacoid molecules
(Able et al., 2014; Cardoso et al., 2014). involved in the active resolution of inflammation, and are
Overall, these studies highlight the unique and indispensable produced through COX and LOX pathways (Serhan et al.,
role of DHA in neuronal membranes, whereas, the only 2008). EPA produces E-series resolvins (RvE), whereas DHA
established unique role for EPA is as a precursor to the produces docosanoids, such as protectins, D-series resolvins
three series eicosanoids and related peroxy-fatty acids, although (RvD) and maresins (MaR; Serhan et al., 2015). Recently
specific therapeutic effects have been putatively identified across analogous mediators to DHA-derived D-series resolvins,
a range of neurological conditions. Similarly, bioactive roles for protectins and MaRs have been identified from DPA, and
DPA are now being described. The remainder of this review will include RvD1n-3 DPA , MaR1n-3 DPA and related products (Dalli
explore the evidence for both specific and complementary effects et al., 2013). PD1n-3 DPA and MaR1n-3 DPA have recently been
of EPA, DPA and DHA in the brain. synthesized and demonstrate potent anti-inflammatory and
pro-resolving properties, with comparable actions to EPA and
EPA, DPA and DHA Derived Lipid DHA-derived resolvins in murine models of acute inflammation
Mediators and human leukocytes (Aursnes et al., 2014; Tungen et al., 2014).
The rapidly expanding repertoire of oxygenated metabolites
It is well established that omega-3 PUFA derived lipid from EPA, DPA and DHA and the similarity between their
mediators play a key role in the inflammatory response. These isomers has the scope for confusion in assigning biological
enzyme-derived mediators are a varied group of oxygenated properties, and it has been suggested that care needs to be taken
forms of the C20 and C22 omega-3 PUFAs. The classic when interpreting the literature (Balas et al., 2014).
lipid mediators include prostaglandins and leukotrienes (LT), The SPMs act via a series of cell-type specific receptors, which
and two structurally distinct new classes of mediators have due to space restraints are beyond the scope of this review;
been identified. The first are called ‘‘Specialized Pro-resolving however, the reader is directed to a number of excellent reviews
Mediators’’ (SPMs; Bannenberg and Serhan, 2010), and the by Dr. Charles Serhan, whose laboratory has led research in this
second are electrophilic fatty acid oxo-derivatives (Groeger et al., area (Serhan et al., 2009; Bannenberg and Serhan, 2010; Dalli
2010; Cipollina et al., 2014). et al., 2013; Serhan and Chiang, 2013). However, by way of a brief
The classic lipid mediators are a varied group of oxygenated example, RvE1 binds the orphan receptor ChemR23, and BLT1 , a
forms, with those derived from the C20 PUFAs, such as leukotriene B4 receptor, whereas RvD1 binds GPR32 and ALX, a
EPA, called eicosanoids, whereas those from C22 DPA lipoxin A4 receptor. This specificity may allow for specific effects
and DHA called docosanoids. Biosynthesis is catalyzed by of EPA, DPA and DHA-derived SPMs. The best characterized
three enzyme systems: cyclooxygenase (COX, also known SPM in terms of nervous system protection is (neuro)protectin
as prostaglandin endoperoxide H synthase or PGHS) and D1 ((N)PD1, 10R-17S-dihydroxy-docosahexaenoic acid), which
subsequent synthases, LOX and cytochrome P450 mixed- is biosynthesized in response to injury and may have therapeutic
function oxidase enzymes (CYP450; Smith et al., 2000). COX potential in a wide range of neurological conditions (Bazan et al.,
catalyzes the initial oxygenation of non-esterified PUFAs to 2011b; Bazan, 2013). The unique neuroprotective potential of
produce prostaglandin H (PGH), a short-lived intermediate, EPA and DPA-derived SPMs remains to be elucidated.
A further novel class of anti-inflammatory lipid mediators brain, the subventricular zone of the lateral ventricles and the
derived from EPA, DPA and DHA has recently been described subgranular layer of the hippocampal dentate gyrus (Ehninger
(Groeger et al., 2010; Cipollina et al., 2014). These are and Kempermann, 2008). Aging is the greatest negative regulator
electrophilic fatty acid oxo-derivates (EFOX) synthesized by of neurogenesis (Kuhn et al., 1996), and there is a strong
COX-2 and 5-LOX, and include 5-oxo-EPA, 7-oxo-DPA correlation between age-related impairments in hippocampal-
and 7-oxo-DHA, from EPA, DPA and DHA, respectively. dependent memory tasks and the decline in neurogenesis
In the first charactrerisation of their actions EFOXs were (Drapeau et al., 2003). Conversely, increased neurogenesis in
shown to have a wide range of anti-inflammatory actions, reported in rodents following ischemia (Takagi et al., 1999),
including acting as agonists of the nuclear transcription factor, stroke (Darsalia et al., 2005) and after seizures (Parent et al.,
peroxisome proliferator-activated receptor gamma (PPARγ), 1997). These increases in neurogenesis may be an attempt
activating Nrf2-dependent antioxidant reponses and inhibiting at brain self-repair and raises the intriguing possibility that
cytokine production and inducible nitric oxide expression in enhancing neurogenesis and the subsequent survival of new
activated macrophages (Groeger et al., 2010). Importantly, neurons may have significant therapeutic potential.
dietary supplementation with 1 g EPA and 0.4 g DHA per day In vitro DHA has consistently been shown to promote the
for 4 months significantly increases the formation of 5-oxo-EPA differentiation of neural stem cells into neurons (Kawakita
and 7-oxo-DHA (Cipollina et al., 2014), and consitent with the et al., 2006; Katakura et al., 2009); however, comparisons of
formation of resolvins from DHA (Serhan et al., 2002), aspirin the pro-neurogeneic effects of different omega-3 PUFAs have
acetylation of COX-2 also significantly increases production of only recently begun to be explored in the literature. In the first
EFOXs. Although independent roles of the different EFOXs direct comparison 1 µM DHA and EPA were both reported to
have yet to be described, these observations suggest these newly enhance differentiation of neural stem cells to a similar extent
reported lipid mediators needs to be considered when assiging (Katakura et al., 2013). However, they had divergent effects on
anti-inflammatory and pro-resolving effects to EPA, DPA and the transcription factors involved in regulating the cell cycle.
DHA. The multiple lipid mediators derived from EPA, DPA and EPA significantly increased the levels of Hes1, whereas with
DHA are summarized in Figure 2. DHA levels were significantly decreased. Hes1 is a repressor type
transcription factor, which inhibits neuronal differentiation and
Effects of EPA, DPA and DHA on Brain enhances proliferation in neural stem cells (Katakura et al., 2013).
Plasticity Also, EPA, but not DHA, significantly increased Hes6, which
acts in a positive-feedback loop with Hes1 to promote neuronal
Neurite Outgrowth and Synaptogenesis differentiation. Preliminary work in our laboratory also suggests
The synapse and nerve growth cone are two structures that divergent effects of EPA and DHA on neurogenesis; however,
play key roles in development and nervous system repair, in this study 10 nM EPA significantly increased proliferation,
furthermore, slow neurodegenerative processes in the CNS are whereas with 10 nM DHA it was decreased, consistent with a
accompanied by significant damage to neurite (Robson et al., role in differentiation (Mandhair et al., 2013). It may be that the
2010). The effects of EPA and DHA, but not DPA have been effects of EPA and DHA in regulating neural stem cell fate are
studied on neurite outgrowth and synaptogenesis in a variety based on a fine balance between their respective effects at basic
of cell types and stages of development. Early studies focused helix-loop-helix transcription factors.
on DHA, and found beneficial effects on neurite outgrowth Although the addition of EPA and DHA show regulatory eff-
in terms of overall length and complexity of outgrowth in ects on neural stem cell fate, it is currently unclear whether
rat pheochromocytoma-12 (PC-12) cells (Ikemoto et al., 1997), these are direct effects of EPA and DHA or their
rat embryonic hippocampal primary cultures (Calderon and metabolites. The DHA endocannabinoid-like metabolite,
Kim, 2004) and rat embryonic cortical neurons (Cao et al., N-docosahexanoylethanolamine (DHEA, also known as
2005). In addition to enhanced neurite outgrowth, DHA also synaptamide) induces neuronal differentiation of neural stem
promotes synaptogenesis and synaptic expression of synapsin, cells by activation of protein kinase A (PKA)/cAMP response
and glutamate receptors in rat hippocampal neurones (Cao et al., element binding protein (CREB; Rashid et al., 2013). Furthermore,
2009). Work in our laboratory directly compared the neurite- the oxygenated DHA-derivative NPD1 has also been shown to
promoting effects of DHA with EPA in primary sensory neuronal promote neuronal differentiation of embryonic stem cells (Yanes
cultures from young (post-natal day 3 and 9), adult (2–4 months) et al., 2010). Overall however, these results suggest that the
and aged (18–20 month) rats (Robson et al., 2010). Both EPA and regulatory effects of EPA and DHA directing neural stem cell fate
DHA increased neurite outgrowth in the developmental stages; are mediated via divergent effects at transcription factors and
however, only DHA produced positive effects in the tissue from potentially different signaling pathways, and may be at least in part
aged rats, which possess a significantly lower degree of plasticity mediated by their enzymatic conversion to bioactive mediators.
than tissues from immature animals.
Normal Brain Aging and Alzheimer’s
Neurogenesis Disease
Adult neurogenesis is the process by which new neurons are
generated from neural stem cells and progenitor cells and has Many widespread changes characterize normal brain aging, such
been consistently shown to occur in two areas of the adult as increased oxidative stress (Perluigi et al., 2014), mitochondrial
FIGURE 2 | Summary of the lipid mediators derived from (A) EPA, (18S-, or 18R-HETE) from EPA, which are either converted by 5-LOX to
(B) DPA and (C) DHA. In the classical “canonical” pathway EPA is initially aspirin-triggered 18S-resolvin E1 and resolvin E1 (AT-18S-RvE1 and
converted to the intermediate prostaglandin G2 (PGG2 ) by either COX-1 or -2 AT-RvE1), respectively, or through an extra step by LTA4 H to AT-18S-RvE2
and then enzymatically to the 3 series prostaglandins, prostacylcins or and AT-RvE2. Analogous series of resolvins, maresins, and EFOXs produced
thromboxanes. EPA can also be converted by 5-lipoxygenase (LOX) to from DPA to those from DHA have recently been identified; however, the
5-hydroperoxyeicosapenataenoic acid (5-H(p)EPE), which can then either be nature of the enzymatic conversions remains to be elucidated. DHA is
converted by 5-LOX to leukotriene A5 (LTA5 ) and then by Leukotriene A4 converted to 17S-hydroperoxydocosahexaenoic acid (17S-H(p)DHA) by
Hydrolase (LTA4 ) to leukotriene B5 (LTB5 ) or to 5-hydroxyeicosapentaenoic 15-LOX, which is converted by 5-LOX to D-series resolvins (RvD), or
acid (5-HEPE), which is then converted into 5-oxo-EPA by enzymatically hydrolysed to (neuro)protectin D1 ((N)PD1. DHA can also be
5-hydroxyeicosanoid dehydrogenase (5-HEDH). EPA can also be sequentially converted by 12 or 15-LOX via 14-hydroperoxydocosahexaenoic acid
converted by cytochrome P450 (CYP450) enzymes to (14-H(p)DHA) to the maresins. DHA can also be converted by 5-LOX to
18R-hydroxyeicosapentaenoic acid (18R-HEPE) and then by 5-LOX to 7-hydroxydocosahexaenoic acid (7-HDHA) and then by a dehydrogenase to
E-series resolvins (RvE). COX-2 can also convert EPA to the electrophilic fatty 7-oxo-DHA, with 5-HEDH a likely candidate, or by COX-2 to EFOX-D6 , which
acid oxo-derivative electrophilic fatty acid oxo-derivates (EFOX)-D5 , in a is enhanced by aspirin acetylation. Acetylation also produces
process enhanced by aspirin acetylation of COX-2. Aspirin acetylation of 17R-hydroperoxyDHA, which can then be converted to aspirin triggered
COX-2 also produces 18S- and 18R-hydroperoxyeicosapentaenoic acids resolvins and protectins.
dysfunction and alterations in energy metabolism (Ames, 2004) of the undetected disease (Fjell et al., 2014). AD is the most
and damage to DNA (Canugovi et al., 2013). There are also common form of dementia in the older person, with a prevalence
age-related structural changes including a reduction in brain of about 4.4% of the population over 65 years of age (Ward
volume and weight (Anderton, 2002) and altered membrane et al., 2012) and affects cognitive function, mood and behavior
lipid content (Svennerholm et al., 1997). The aging brain is (Selkoe et al., 2012). The characteristic pathological features
more prone to the development of neurodegenerative diseases, of AD are neurofibrillary tangles, which are mainly composed
such as Alzheimer’s disease (AD), and with the slow developing of aggregates of hyperphosphorylated tau protein and senile
preclinical phases of these diseases it may be difficult to plaques containing amyloid β-protein (Aβ; Lloret et al., 2015).
distinguish what are age-related changes and what are effects The etiology and pathogenesis of the disease is currently not
well understood, and management is mostly symptomatic, aimed patients (Astarita et al., 2010). Liver DHA content was lower
at ameliorating the cognitive deficits (Selkoe et al., 2012). in AD patients than control subjects, whereas EPA, DPA and
Furthermore, a recent meta-analysis has shown that relatively tetracosahexaenoic acid (24:6n-3), were significantly elevated.
few clinical trials are being undertaken for AD therapeutics, and Consistent with these changes, expression of peroxisomal
the number of compounds progressing to regulatory review is D -bifunctional protein was reduced; suggesting decreased activity
among the lowest found in any therapeutic area (Cummings of this enzyme is involved in impaired DHA biosynthesis, thereby
et al., 2014), highlighting the importance of developing new lessening the flux to the brain. However, the relative contribution
therapeutic approaches in this area. of DHA biosynthsized by the liver compared to that provided by
dietary intake remains to be established, as does the overall effect
Fatty Acid Composition of this on blood DHA levels.
Several studies have investigated the relationship between blood
EPA, DPA and DHA levels and risk of cognitive decline. Higher Inflammation, Learning and Memory
plasma EPA, but not DHA, was found to be associated with lower The aging brain is particularly prone to inflammatory and
gray matter atrophy of the hippocampal/parahippocampal area oxidative alterations, which may underlie decreases in learning
and amygdala of community dwellers aged 65 years and older and memory, as manifested in the age-related deficits in
(Samieri et al., 2012), and higher plasma EPA, but not DPA or long-term potentiation (LTP; Lynch, 2004). LTP is an
DHA, was also associated with slower cognitive decline (Samieri electrophysiological property of certain neuronal circuits
et al., 2011), dementia risk (Samieri et al., 2008) and depressive that is used as a model for investigation of the pathways
symptom risk in the elderly (Feart et al., 2008). Furthermore, a underlying activity driven neuronal and synaptic plasticity,
recent meta-analysis found that although blood EPA, DHA and learning and memory (Bliss and Collingridge, 1993). Dietary
total omega-3 PUFA are significantly decreased in patients with enrichment of aged-rats with EPA, DHA and more recently
dementia, only EPA was significantly lower in patients with pre- DPA have all been shown to have positive effects on age-related
dementia syndrome, leading the authors to suggest that EPA may impairments in LTP, and these effects are likely mediated via
by a biomarker and indeed risk factor for age-related cognitive multiple anti-inflammatory effects acting via alterations in
impairment (Lin et al., 2012a). However, others have shown a cytokine levels. For example, 8 weeks dietary supplementation
reduced risk of developing all-cause dementia associated with with 10 mg/day DHA reverses age-related impairments in
higher plasma DHA, not EPA (Schaefer et al., 2006). In this study LTP and depolarization-induced glutamate release (McGahon
those in the top quartile of plasma PC DHA level were associated et al., 1999). Similarly, feeding rats diets supplemented with
with a significant 47% reduction in risk. Furthermore, a recent EPA for 8 weeks (10 mg/day for 3 weeks and 20 mg/day
cross-sectional analysis of 1575 dementia-free participants also for 5 weeks) prevented age-related increases in cortical and
found only lower erythrocyte DHA, but not EPA, associated hippocampal IL-1β and restores LTP (Martin et al., 2002),
with significantly smaller brain volumes and lower scores in age-related increases in IL-1β-induced signaling and decreases
tests of visual memory, executive function and abstract thinking in IL-4, and extracellular-signal-regulated kinases (ERK) and
(Tan et al., 2012). These inconsistencies between observations are PI-3 kinase (Maher et al., 2004). 125 mg/day EPA for 4 weeks
likely due to the issues described above limiting the efficacy of also attenuated age-related increases in hippocampal IL-1β,
using blood fatty acid levels as a surrogate biomarker for CNS interferon-γ, and decreases in IL-4 (Lynch et al., 2007). EPA also
levels. protects aged rats from amyloid-β (Aβ) induced increases in
In order to address some of these issues, a recent innovative hippocampal IL-1β, potentially mediated by positive effects on
study investigated the differences in fatty acid content of matched the PPARγ nuclear transcription factor (Minogue et al., 2007).
plasma and brain cortex samples from post-mortem samples This group also recently compared the effects of DPA with EPA,
from subjects with no cognitive impairment, mild cognitive where similar neuroprotective effects were reported (Kelly et al.,
impairment and AD (Cunnane et al., 2012). To date this has been 2011). In this study both DPA and EPA (200 mg/kg/day) were
the only study to directly compare plasma and brain levels from equally potent at reversing age-related impairment in spatial
the same subjects. In the AD group DHA, but not EPA or DPA, learning and LTP, and showed similar abilities to decreases
was found to be higher in the plasma cholesteryl esters and lower in age-related microglial activation and associated oxidative
in plasma phospholipids. In the brain, DHA was lower only in stress.
PS of the mid-frontal cortex and superior temporal cortex of AD Significant advances have been made in our understanding of
subjects compared to non-cognitively impaired. Interestingly, the role of DHA and DHA-derived anti-inflammatory mediators
there was only one significant correlation between plasma and such as neuroprotection (NPD-1) in brain cell survival and repair
brain fatty acid samples and this was between DHA in plasma in the aging and AD brain (e.g., Bazan et al., 2011a). However,
total lipids and DHA in PE of the angular gyrus, but this was only few studies have made direct comparisons with EPA or DPA
seen in the subjects with mild cognitive impairment. Overall, or their metabolites. A recent study has however compared
these results suggest that the fatty acid content of plasma from the relative anti-inflammatory effects of EPA and DHA in
subjects with mild cognitive impairment or AD may not reflect vitro in peripheral blood mononuclear cells from AD patients
the content of the brain cortex. compared with healthy controls (Serini et al., 2012). The addition
Astatrita and coworkers investigated the role of liver DHA of either EPA or DHA (10–20 µM) significantly reduced the
biosynthesis in the altered brain DHA content seen with AD induced-cytokine release. Although DHA consistently showed
a more pronounced effect than EPA, DHA reduced only the Overall, where individual omega-3 PUFAs have been
high IL-1β/IL-10 ratio, whereas EPA also reduced the IL-6/IL-10 investigated in trials of healthy aging, mild cognitive impairment
ratio. Overall, DHA had a more powerful inhibitory effect on and AD the focus has been on DHA, which is consistent with
individual inflammatory cytokines; however, EPA was better the pre-clinical evidence (Dyall and Michael-Titus, 2008). DHA
at changing the proinflammatory profile of the cells from treatment appears to show the greatest promise compared to EPA
AD patients to a profile closer to that found in the healthy and DPA, and the beneficial of DHA treatment currently appear
controls. to be to improve memory and learning in participants with
MMSE scores above 26–27, particularly non-ApoE-ε4 carriers,
Clinical Trials although support from clinical trials is currently extremely
To date clinical trials with omega-3 PUFAs in healthy older limited.
adults, individuals with mild cognitive impairment or AD have
tended to use mixed EPA and DHA preparations at different Parkinson’s Disease
ratios, and have been reviewed extensively elsewhere (Jiao
et al., 2014). There have however been a limited number of Parkinson’s disease (PD) is the second most common
trials using either highly enriched EPA or DHA preparations. neurodegenerative disorder after AD and has a prevalence
An early open-label pilot study treated AD patients (MMSE of about 2% in the older person, and is also associated
scores 10–24) aged 65 and over with 1 g/day EPA treatment with aging (Franco-Iborra et al., 2015). PD affects the basal
for 12 weeks (Boston et al., 2004). This short-term treatment ganglia with patients typically experiencing slowed movements
significantly increased erythrocyte EPA and DPA, but not DHA, (bradykinesia), muscle stiffness (rigidity), tremor and disturbed
and there was no difference between treatment and baseline balance (Franco-Iborra et al., 2015). The neuropathology of the
scores in cognitive measures. In a more recent randomized-blind, disease includes dopaminergic neuronal loss from the substantia
placebo-controlled study participants with mild to moderate AD nigra pars compacta as well as the presence of Lewy bodies,
(MMSE scores 14–26) were supplemented with 2 g/day DHA for which are intracellular inclusions largely composed of the
18 months (Quinn et al., 2010). The DHA supplementation did protein, α-synuclein (Kim et al., 2014b). The pathology and
not slow the rate of cognitive decline compared to the placebo, clinical features of PD and AD are markedly different; however,
although there may have been weak effects with ApoE-ε4 non- they do share common mechanism, including mitochondrial
carriers. dysfunction (Camilleri and Vassallo, 2014), neuro-inflammation
More positive effects have been seen in cognitively healthy (Sanchez-Guajardo et al., 2015), and oxidative stress (Xie
participants and participants with mild cognitive impairment. et al., 2014). Current symptomatic treatment of PD is based
Yurko-Mauro and colleagues supplemented healthy adults aged on correcting dopaminergic signaling, using medications such
55 years and over with MMSE scores above 26 with 900 mg as carbidopa/levodopa, dopamine agonists. However, a large
DHA or placebo for 24 weeks (Yurko-Mauro et al., 2010). number of patients develop mild to moderate, and occasionally
The treatment significantly improved Paired Associate Learning serious, treatment-associated side-effects, significantly limiting
(PAL, six pattern errors) and immediate and delayed Verbal the efficacy of these treatments (Faulkner, 2014).
Recognition Memory scores, and plasma DHA levels doubled
and correlated with improved PAL scores in the DHA group. Fatty Acid Composition
Similarly, participants with mild cognitive impairment and aged Purified lipid rafts from the frontal cortex of postmortem samples
60 years and over were given either 1.3 g DHA and 0.45 mg from patients with early motor stage PD and incidental PD
EPA or placebo for 12 months and those in the DHA treatment exhibit significant reductions in DHA (and AA), but not EPA
group had significant improvements in short-term and working or DPA, compared to controls (Fabelo et al., 2011). Whereas, no
memory, immediate verbal memory and delayed recall memory differences in the levels of EPA, DPA or DHA were found in
compared to the placebo group (Lee et al., 2013). These results are post-mortem analysis of temporal cortex tissue from levodopa-
consistent with a study showing positive effects in a sub-group of treated PD patients, or monkeys treated with the Parkinsonian
patients with very mild cognitive impairment (MMSE > 27) who neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
were given a high DHA supplement (1.7 g DHA and 0.6 g EPA) (MPTP), compared to their respective matched controls (Julien
for 6 months (Freund-Levi et al., 2006). et al., 2006). However, significant decreases in DHA were seen
There has only been one study to directly compare the in the temporal cortical fatty acid profile of primates treated
effects of DHA with EPA in participants with mild cognitive with the MPTP following dyskinesiogenic levodopa treatment,
impairment (Sinn et al., 2012). In this 6 month double-blind suggesting the decrease in DHA may be related to the appearance
randomized controlled trial participants received a supplement of dyskinesia (Julien et al., 2006).
high in EPA (1.67 g EPA and 0.16 g DHA), high in DHA (1.55 g
DHA and 0.40 g DHA) or high in the omega-6 PUFA linoleic acid Pre-Clinical Studies
(2.2 g). Compared to the linoleic acid group both the EPA and Although there have to date been no clinical trials reported with
DHA groups significantly improved their Geriatric Depression supplementation of highly enriched EPA, DPA or DHA in the
Scores, but only with the DHA group were changes memory treatment PD there have been a number of in vitro and in vivo
seen, where there were significant improvements in verbal studies. Mice were fed for 6 weeks a diet providing 0.8% EPA,
fluency. and their brain slices treated with the Parkinsonian neurotoxin
1-methyl-4-phenylpyridinium (MPP(+)) (Meng et al., 2010). (Dyall et al., 2010). Moreover, Lengqvist and coworkers have
EPA treatment attenuated the MPP(+) induced increase in AA shown that other PUFAs such as DPAn-6 and AA are able to
content, partially attenuated the striatal dopaminergic turnover, bind and activate RXR in the same range as DHA, indicating RXR
and prevented the increases of the pro-apoptotic bax and activation is not restricted to DHA, but may also extend to EPA
caspase-3 mRNAs. The treatment significantly increased tissue and DPA.
EPA and DPA, but not DHA levels, suggesting the effects may Overall, there is a lack of clinical trials investigating the role
have been mediated directly by EPA and/or DPA. Following of EPA, DPA or DHA in PD, although pre-clinical evidence
the same dietary paradigm the same group investigated the suggests that EPA may possess therapeutic potential, and may
effects of EPA in the (MPTP)-probenecid (MPTP-P) mouse provide useful adjunctive treatments by alleviating the treatment-
model of PD (Luchtman et al., 2012). EPA treatment attenuated associated dyskinesias. However, a 12 week double-blind placebo
the MPTP-P induced hypokinesia, ameliorated the procedural controlled study providing 2 g/day EPA in schizophrenia patients
memory deficit and also suppressed the production of striatal with established tardive dyskinesia failed to demonstrate any
pro-inflammatory cytokines. However, EPA did not prevent anti-dyskinetic effects, although modest and transient benefits
nigrostriatal dopamine loss. The mechanisms behind these were seen in recent onset patients (Emsley et al., 2006). A
neuroprotective effects of EPA were explored in vitro by the clinical trial is currently exploring the role of DHA in reducing
same group (Luchtman et al., 2013). In MPP(+) treated cells, dyskinesia in PD (ClinicalTrials.gov identifier: NCT01563913),
EPA was shown to attenuate the reduction in cell viability and and should help clarify this issue with DHA at least. It is also
prevent the presence of cytoplasmic inclusions. EPA treatment important to appreciate that DHA supplementation may have
also had widespread protective effects, such as attenuating the the potential to worsen the condition. The cytotoxic α-synuclein
MPP(+)-induced increase in Tyrosine-related kinase B (TrkB) aggregating induced by DHA in a variety of models suggests
receptors, and down-regulated reactive oxygen species and nitric that caution should be exerted when considering the role of
oxide, an effect potentially mediated by inhibition of neuronal EPA, DPA and DHA in PD and this area warrants much further
NADPH oxidase and COX-2. EPA also attenuated an increase research.
in the bax:bcl-2 ratio, and cytochrome c release. The effects
of DHA have been explored in MPTP monkeys, where DHA Conclusions
(100 mg/kg) reduced dyskinesias induced by levodopa without
affecting the anti-Parkinsonian effects, suggesting DHA may This article has reviewed evidence for individual and shared
delay the development dyskinesias induced by levodopa, or at neuroprotective effects of EPA, DPA and DHA in aging
least reduce their severity (Samadi et al., 2006). Protective effects and neurodegenerative disorders. EPA, DPA and DHA differ
of DHA have also been shown in mice given a high DHA in important aspects of their biochemistry and metabolism;
diet (5.3 g/kg DHA) and then treated with MPTP (Bousquet however, few studies have made direct comparisons between
et al., 2008). Following the DHA treatment the dopamine levels their effects. DHA is quantitatively the most important omega-3
were preserved and the substantia nigral dopaminergic neurons PUFA in the brain and has consistently been shown to have
were protected against losses compared to the controls; however, unique and indispensable roles in the neuronal membrane.
motor behavior was not measured. However, independent effects for EPA and DPA are being
It should however be noted that DHA treatment may identified, particularly in regards to their respective anti-
potentially increase α-synuclein aggregation and the possible inflammatory mediators. A more detailed characterization of the
formation of cytotoxic oligomers (De Franceschi et al., individual properties of these mediators, their cognate receptors
2011; Yakunin et al., 2012). α-Synuclein is a neuronal and downstream targets may prove essential to increasing
protein that accumulates progressively in PD and related understanding of their specific actions.
synucleinopathies. In models systems DHA readily promotes Deficits in EPA and DHA levels have been found with
α-synuclein aggregation in Escherichia coli cells transfected neurodegenerative disorders; however, these have been identified
with the human α-synuclein (De Franceschi et al., 2011). with varying consistency across studies, and may require a
The α-synuclein oligomers were more toxic if generated in more detailed appreciation of the role of genetic variability
the presence of DHA in dopaminergic neuronal cell lines. before a clear picture arises. Although promising therapeutically,
Furthermore, transgenic mice with the PD-causing A53T direct evidence from large well-designed intervention studies
α-Syn mutation fed a diet enriched with 0.69% DHA showed into the effects of EPA, DPA and DHA in normal aging and
increased accumulation of soluble and insoluble neuronal neurodegenerative disorders is still lacking; however, preliminary
α-synuclein, neuritic injury and astrocytosis (Yakunin et al., evidence suggests the greatest benefit may been seen with
2012). These α-synuclein oligomers have also been shown DHA in non-cognitively impaired older people. It is vital to
alter membrane permeability in cellular membrane-mimetic consider omega-3 PUFA specific effects when designing and
and cell model systems (Fecchio et al., 2013). Further undertaking systematic reviews and meta-analyses, so treatment
in vitro analysis suggests that the enhanced α-synuclein effects are not lost in the aggregation of results. Overall, a greater
oligomerisation in response to DHA is mediated via the retinoic understanding of the individual roles of EPA, DPA and DHA in
X receptor (RXR). DHA is an endogenous ligand of RXRs brain health, protection and repair is needed in order to make
(de Urquiza et al., 2000; Egea et al., 2002; Lengqvist et al., 2004) appropriate dietary recommendations and targeted therapeutic
and aged rats treated with DHA show enhanced RXR expression interventions.
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between raft and nonraft domains. Biophys. J. 103, 228–237. doi: 10.1016/j.bpj. conducted in the absence of any commercial or financial relationships that could
2012.06.016 be construed as a potential conflict of interest.
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α-synuclein neuropathology is controlled by nuclear hormone receptors and are credited and that the original publication in this journal is cited, in accordance
enhanced by docosahexaenoic acid in a mouse model for Parkinson’s disease. with accepted academic practice. No use, distribution or reproduction is permitted
Brain Pathol. 22, 280–294. doi: 10.1111/j.1750-3639.2011.00530.x which does not comply with these terms.