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Docosahexaenoic acid,22:6n-3 (DHA) and its metabolites are vital for the structure and functional brain development of the fetus and infants, and also for maintenance of healthy brain function of adults. DHA is thought to be an essential nutrient required throughout the life cycle for the maintenance of overall brain health. The mode of actions of DHA and its derivatives at both cellular and molecular levels in the brain are emerging. DHA is the major prevalent fatty acid in the brain membrane. The brain maintains its fatty acid levels mainly via the uptake of plasma free fatty acids. Therefore, circulating plasma DHA is significantly related to cognitive abilities during ageing and is inversely associated with cognitive decline. The signaling pathways of DHA and its metabolites are involved in neurogenesis, antinociceptive effects, anti-apoptotic effect, synaptic plasticity, Ca2+ homeostasis in brain diseases, and the functioning of nigrostriatal activities. Mechanisms of action of DHA metabolites on various processes in the brain are not yet well known. Epidemiological studies support a link between low habitual intake of DHA and a higher risk of brain disorders. A diet characterized by higher intakes of foods containing high in n-3 fatty acids, and/or lower intake of n-6 fatty acids was strongly associated with a lower Alzheimer's Disease and other brain disorders. Supplementation of DHA improves some behaviors associated with attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior, as well as cognition. Nevertheless, the outcomes of trials with DHA supplementation have been controversial. Many intervention studies with DHA have shown an apparent benefit in brain function. However, clinical trials are needed for definitive conclusions. Dietary deficiency of n-3 fatty acids during fetal development in utero and the postnatal state has detrimental effects on cognitive abilities. Further research in humans is required to assess a variety of clinical outcomes, including quality of life and mental status, by supplementation of DHA.
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International Journal of Developmental Neuroscience
journal homepage: www.elsevier.com/locate/ijdevneu
Review
Docosahexaenoic acid,22:6n-3: Its roles in the structure and function of the
brain
Rahul Mallick
a
, Sanjay Basak
b
, Asim K. Duttaroy
c,
a
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
b
ICMR-National Institute of Nutrition, Hyderabad, India
c
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Norway
ARTICLE INFO
Keywords:
Docosahexaenoic acid,22:6n-3
Cognitive
Brain development
Endocannabinoid system
Marine oil
Neurogenesis
Resolvins
Clinical trials
DHA uptake
FABPs
Brain disorders
ABSTRACT
Docosahexaenoic acid,22:6n-3 (DHA) and its metabolites are vital for the structure and functional brain de-
velopment of the fetus and infants, and also for maintenance of healthy brain function of adults. DHA is thought
to be an essential nutrient required throughout the life cycle for the maintenance of overall brain health. The
mode of actions of DHA and its derivatives at both cellular and molecular levels in the brain are emerging. DHA
is the major prevalent fatty acid in the brain membrane. The brain maintains its fatty acid levels mainly via the
uptake of plasma free fatty acids. Therefore, circulating plasma DHA is signicantly related to cognitive abilities
during ageing and is inversely associated with cognitive decline. The signaling pathways of DHA and its me-
tabolites are involved in neurogenesis, antinociceptive eects, antiapoptotic eect, synaptic plasticity, Ca
2+
homeostasis in brain diseases, and the functioning of nigrostriatal activities. Mechanisms of action of DHA
metabolites on various processes in the brain are not yet well known. Epidemiological studies support a link
between low habitual intake of DHA and a higher risk of brain disorders. A diet characterized by higher intakes
of foods containing high in n3 fatty acids, and/or lower intake of n6 fatty acids was strongly associated with a
lower Alzheimer's Disease and other brain disorders. Supplementation of DHA improves some behaviors asso-
ciated with attention decit hyperactivity disorder, bipolar disorder, schizophrenia, and impulsive behavior, as
well as cognition. Nevertheless, the outcomes of trials with DHA supplementation have been controversial. Many
intervention studies with DHA have shown an apparent benet in brain function. However, clinical trials are
needed for denitive conclusions. Dietary deciency of n3 fatty acids during fetal development in utero and the
postnatal state has detrimental eects on cognitive abilities. Further research in humans is required to assess a
variety of clinical outcomes, including quality of life and mental status, by supplementation of DHA.
1. Introduction
α-Linolenic acid,18;3n-3 (ALA) and linoleic acid, 18:2n-6 (LA) are
the two essential fatty acids for human health. ALA is available in plant
oils, e.g., walnut, edible seeds (hemp, chia), canola, kukui, axseed oil
and hemp oil whereas its long-chain polyunsaturated fatty acids
(LCPUFAs) eicosapentaenoic acid,20:5n-3 (EPA) and docosahexaenoic
acid, 22:6n-3 (DHA) are obtained from marine sh and oils. In healthy
young adults, consumed ALA from the diet can be converted into EPA
and DHA in little amount (Burdge and Wootton, 2002), but with age,
the conversion capability is reduced (Bradbury, 2011). DHA is, there-
fore, a conditionally essential fatty acid for human health. DHA inu-
ences numerous processes in the body, e.g., signal transduction, mem-
brane structure and function, cellular proliferation, inammation,
https://doi.org/10.1016/j.ijdevneu.2019.10.004
Received 22 August 2019; Received in revised form 10 October 2019; Accepted 11 October 2019
Abbreviations: AA, arachidonic acid; AD, Alzheimers disease; ADHD, attention decit hyperactivity disorder; ALA, α-linolenic acid, 183n-3; APOE, apolipoprotein E;
B-FABP, brain-fatty acid-binding proteins; COX, cyclooxygenase; CYP, cytochrome P450; DHA, docosahexaenoic acid,226n-3; EDPs, epoxydocosapentaenoic acids;
EPA, eicosapentaenoic acid,205n-3; EFOX, electrophilic oxo-derivatives; FABP, fatty acid-binding proteins; FAHFA, fatty acid esters of hydroxy fatty acids; FADS2,
delta 6 desaturase enzyme; GPRs, G-protein coupled receptors; H-FABP, heart-fatty acid-binding proteins; HPA, hypothalamus-pituitary-adrenal; HDoHE, hydro-
xydocosahexaenoic acids; HpDHA, DHA hydroperoxides; LCPUFA, long-chain polyunsaturated fatty acids; MaR1, maresin 1; NPD1, neuroprotectin D1; LOX, li-
poxygenases; NO, nitric oxide; PEMT, phosphatidyl ethanolamineNmethyltransferase; p-FABPpm, placental plasma membrane fatty acid-binding protein; PPAR,
peroxisome proliferator-activated receptor; PPAR-α, peroxisome proliferator-activated receptor α; PPAR-γ, peroxisome proliferator-activated receptor gamma;
PUFAs, polyunsaturated fatty acids; RXR, retinoid X receptor specialized pro-resolving mediators
Corresponding author at: Faculty of Medicine, University of Oslo, P.O.B. 1046 Blindern, N-0316, Oslo, Norway.
E-mail address: a.k.duttaroy@medisin.uio.no (A.K. Duttaroy).
International Journal of Developmental Neuroscience 79 (2019) 21–31
Available online 17 October 2019
0736-5748/ © 2019 ISDN. Published by Elsevier Ltd. All rights reserved.
T
angiogenesis and host of other processes aecting health and disease
(Basak et al., 2013;Bradbury, 2011;Quinn et al., 2010b). DHA meta-
bolites also play a signicant role in dierent biological and cellular
processes. Risk of inammatory disorders, cognitive disorders, in-
sucient brain growth and development may occur due to low intake
of DHA and its precursor EPA (Quinn et al., 2010b). DHA is also re-
commended to treat cardiovascular disease (CVD) risk factors such as
hypercholesterolemia, hypertriglyceridemia, and hypertension (Mori
et al., 2000a,b). Higher intake of DHA is usually recommended to
prevent CVD. EPA is mostly involved in cell signalling, whereas DHA is
mainly used for cell membrane structure and function (Bradbury, 2011;
Innis, 2008). However, recently several studies demonstrated the sig-
nalling pathways of DHA metabolites in the brain. A signicant number
of reviews are available on DHA and human brain (Bradbury, 2011;
Brenna and Carlson, 2014;Salem and Eggersdorfer, 2015;Sun et al.,
2018). This review describes the roles of DHA and its metabolites in the
structure and function of the human brain.
2. DHA uptake and metabolism in human
DHA is mostly deposited in the brain and retina, whereas its dis-
tribution in other tissues such as heart, liver, skeletal muscle, adipose
tissue, blood cell is low. The most signicant n-3 fatty acid present in
the brain is DHA, whereas EPA and ALA are present in very small
amounts. DHA constitutes over 90% of the n-3 PUFAs in the brain and
constitutes 10%20% of its total lipids (Brenna and Carlson, 2014).
DHA is especially found in the grey matter (Suzuki et al., 1997). In a
cellular context, DHA is esteried into the cell membrane phospholipids
mostly in phosphatidylethanolamine and phosphatidylserine and other
complex lipids (Calder, 2016). Following insertion into the cell mem-
brane, DHA interacts with cholesterol that inuences the membrane
phospholipid width by packing constraints and conformation of ad-
jacent phospholipid acyl chains (Sherratt and Mason, 2018). Physical
nature of DHA increases electron density in the phospholipid head
group region within the cell membrane, which attributes rapid con-
formational changes. Owing to the unique structure, DHA is capable of
providing a wide range of cell membrane structure and functions. Thus,
DHA aects dierent biophysical characteristics and physiological
processes such as membrane uidity, lipid raft function, neuro-
transmitter release, membrane receptors, gene expression, signaling
pathways, myelination, inammation, and cell growth and dier-
entiation (Duttaroy, 2016;OBrien and Sampson, 1965;Sun et al.,
2018;Suzuki et al., 1997). Depending on the maternal supply of ALA,
EPA or DHA, DHA accumulates in the fetal brain during the last period
of pregnancy. The brains frontal lobes are more responsive to DHA
supply in adolescent and older adults for executive and higher-order
cognitive activities (Goustard-Langelier et al., 1999).
EPA plays a dominant role in inhibiting delta-5-desaturase enzyme-
mediated production of the arachidonic acid,20:4n-6(AA). Therefore,
the AA derived pro-inammatory eicosanoids (prostaglandins, throm-
boxanes, leukotrienes) are inhibited by EPA intake in the diet. Also,
EPA competes with AA for phospholipase A
2
enzyme. These are unique
roles of EPA whereas DHA neither ts the catalytic site of delta-5-de-
saturase enzyme nor competes with AA for phospholipase A
2
enzyme
due to its massive spatial structure. Unlike DHA, EPA level is not high
enough in the brain to contribute to neurological function. EPA is re-
ported to be rapidly oxidized in the brain (Chen et al., 2009).
While EPA inhibits the delta-5-desaturase enzyme that directly in-
hibits AA, DHA inhibits another role-playing enzyme delta-6-desaturase
enzyme that involves in LA metabolism (Sato et al., 2001). Due to more
massive spatial structure, DHA sweeps out a higher volume of uid in
the membrane than EPA which increases in membrane uidity for
critical synaptic vesicles and the retina to transmit signals from the
surface of the membrane to the interior of the nerve cells. DHA may also
involve in the breakup of lipid rafts in membranes due to its continuous
sweeping motion (Chapkin et al., 2008). As a result, cancer cells cannot
survive, and inammatory cytokines struggle to initiate signaling re-
sponses (Li et al., 2005). The spatial characteristics of DHA cause an
increase in the LDL particle sizes comparatively, which reduces the
entry of LDL particles into arterial muscle cells to develop athero-
sclerosis lesions (Mori et al., 2000a).
3. Dietary and metabolic sources of DHA and its worldwide
consumption
DHA and EPA are present together ubiquitously in marine mammals
and plant plankton, whereas all terrestrial plants contain ALA. DHA and
EPA are present in marine sources as triacylglycerols and phospholi-
pids. Usually, 100 g of cooked salmon sh contains 5001500 mg DHA.
Caviar, anchovies, mackerel, and herring are the other high sources of
DHA (Agriculture, 2005). Beef, lamb, pork, and chicken contain around
0.02 gm of DHA per 100 gm of meat (Calder, 2016). Although DHA is
mainly obtained from marine sh sources, nowadays, DHA is com-
mercially manufactured from microalgal sources such as Crypthecodi-
nium cohnii and Schizochytrium (Ulven and Holven, 2015). The meta-
bolic biosynthesis of DHA via a series of elongation, desaturation, and
beta-oxidation reactions from EPA is known as Sprechers Shunt
(Burdge et al., 2002;Burdge and Wootton, 2002). Maternal DHA sup-
plementation can contribute to brain and visual development and
function of the fetus and the infant. Maternal breast milk also contains
DHA around 0.32% of total fatty acid (Calder, 2016). N-3 LC-PUFA
dietary supplements are widely available, usually in the triacylglycerol,
non-esteried fatty acid, and ethyl ester forms. The sh oil supplements
are reported not only have n-3 LCPUFA contents well below those
claimed by labels but are also considerably oxidized(Albert et al.,
2015); however, the associated health implications of consuming oxi-
dized LCPUFAs are unclear(Myhrstad et al., 2016)
The human body converts ALA to EPA and DHA via desaturases and
elongases pathways. ALA and LA compete for the same desaturase and
elongase in order to form their respective LCPUFA metabolites (Chilton
et al., 2014;Duttaroy, 2009). Low levels of vitamin B6, magnesium,
zinc and ageing reduce the delta 6 desaturase activity. The activity of
delta-6-desaturase is also blocked by trans fats, present in hydrogenated
oils, fast foods, and many packaged foods. The delta 6 desaturase ac-
tivity is decreased in chronic alcoholism and in diabetes. Delta 5 de-
saturase is inhibited by deciencies of vitamin C, niacin and zinc.
Higher intakes of LA can dominate these enzymes, especially the delta 6
desaturase enzyme (FADS2); thus biosynthesis of EPA and DHA from
ALA is reduced. So, consumption of the higher amount of ALA can in-
crease DHA level to some extent; however, this may not increase plasma
DHA in humans suciently (Neet al., 2010;Plourde and Cunnane,
2008). Fig. 1 shows the conversion of dietary ALA to EPA and DHA. In
order to increase the DHA level in the body, dietary supplementation of
DHA is the most preferred strategy (Cunnane et al., 2013). The synth-
esis of DHA from ALA by elevating levels of enzymes such as FADS2 and
elongase 2 by curcumin is promising. Interestingly, curcumin also en-
hances DHA absorption (Wu et al., 2015). Curcumin is widely con-
sumed as a cooking spice in Indian sub-continent; therefore, the low
intake of DHA in this population may be compensated by the curcumin
intake. Another nutraceutical, quercetin enhanced the anti-in-
ammatory eects of DHA on LPS-stimulated inammatory response in
microglial cells (Sun et al., 2019). These studies indicate that the cer-
tain phytochemicals may enhance the synthesis, bioavailability and
functionalities of DHA; however, further work is required to promote
the role of these phytochemicals in DHA mediated human health ef-
fects.
Retro-conversion of DHA to EPA occurs in the peroxisomes via β-
oxidation to remove the double bond at position 4. Retro-conversion of
DHA is more common in non-neural cells than neural cells (Park et al.,
2016). However, recently it was shown that increased plasma level of
EPA in human following DHA supplementation did not occur via retro-
conversion rather a result of slowed metabolism and/or accumulation
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
22
of plasma EPA (Metherel et al., 2019). During the last 30 years or so,
the increasing incidence of several metabolic diseases are thought to be
due to the results of high dietary intake of n-6 fatty acid containing
foods and oils compared with n-3 fatty acids, thus increased the ratio of
n-6:n-3 fatty acids (20:1) intake to a much higher level than the re-
commended ratio for optimal health benets (Simopoulos, 2016).
DHA intake among developed countries varies a lot. DHA intake is
the highest among the people in Iceland (793.4 mg/day). Even in the
USA, daily DHA intake is around 3.5 times lower than that of Iceland.
Among the Scandinavian countries, Danish people consume the highest
level of DHA (232.3 mg/day). The highest and lowest DHA consump-
tion levels in developing countries by the people of Maldives
(1409.3 mg/day) and Ethiopia (7.01 mg/day) respectively. Estimated
dietary intake indicate that the people from India consume only
52.1 mg DHA/day, while people from Bangladesh consume 167 mg
DHA/day through diet. Pakistanis (24 mg/day) and Nepalese (23.2 mg/
day) consume the lowest level of DHA among all South-Asian countries
(Forsyth et al., 2016). Overall, the daily intake of DHA as a per cent of
daily total energy intake (% energy) from food sources is highest in
Japan (0.152%) followed by China (0.090%), USA and Canada
(0.055%). The people from Oceania and Europe continents consume
0.052% DHA of total energy intake. However, these data had several
limitations including the fact that the data did not directly measure
food consumption but instead reected the food supply in a certain
country and might not accurately reect the real intake of DHA. DHA
consumption is lowest in low-income countries (Forsyth et al., 2016).
The countries having access to coastal areas consume a greater amount
of seafood, and therefore, dietary intake of DHA in these countries is
quite higher than other countries comparatively. N-3 PUFA intake of
0.52.0% of total energy is recommended for adults. Dietary intakes of
0.1-0.18% DHA of total energy for infants above six months old and
1012 mg of DHA/Kg body weight for infants aged up to six months are
recommended (WHO and FAO, 2008). Pregnant or breastfeeding mo-
thers are advised to consume 200 mg of DHA, or 300900 mg of com-
bined EPA and DHA per person per day. Vegetarians and vegans can
take microalgae supplements that contain DHA (Davis and Kris-
Etherton, 2003;Yurko-Mauro et al., 2010). The European Food Safety
Authority (EFSA) recommended a maximum dose of 5 g/day of
EPA + DHA as safe (EFSAReport, 2019).
4. DHA and its impact on the structure and function of the brain
As a crucial structural membrane component of the brain, DHA is
present in the cerebral cortex, synaptic membrane regions, retinal mi-
tochondria, and photoreceptors. Brain and retina tissues contain around
40% and 60% DHA of total PUFAs, respectively. DHA is present in high
amounts in retinal photoreceptors and is therefore essential for visual
function(Liu et al., 2011). Animal studies and human observational
studies have suggested that there is an inverse relationship between
dietary intake of n-3 LCPUFAs and the risk of developing agerelated
macular degeneration. The data from intervention trials have been
mixed, although the delayed progression of an intermediate type of
agerelated macular degeneration was reported earlier (Huang et al.,
2008). The later studies did not nd any positive eect on the age-
related macular after supplementation with n-3 LCPUFAs (Souied et al.,
2015;Wu et al., 2017). The X-linked retinitis pigmentosa was shown to
be improved with DHA supplementation (Homan et al., 2004). The
recent clinical trial did not observe such improvement for X-linked re-
tinitis pigmentosa(Homan et al., 2014). However, some positive ef-
fects, such as the reduced elevation in nal dark-adapted thresholds and
slowed loss of the visual eld sensitivity, were observed (Homan et al.,
2015).
Neuronal cell membranes contain approximately 50% DHA (Calder,
2016;Singh, 2005). DHA contributes around 15% of the total fatty acid
composition in the adult prefrontal cortex. DHA is important for hip-
pocampal and cortical neurogenesis, neuronal migration, and out-
growth (Calderon and Kim, 2004;Cao et al., 2005;Kawakita et al.,
2006). DHA suppresses cell death by promoting cell-cycle exit in neuro-
progenitor cells (Insua et al., 2003;Kawakita et al., 2006). Along with
other fatty acids, DHA has a signicant role in monoaminergic and
cholinergic systems during brain development (Aïd et al., 2003;Chalon,
2006;Innis, 1991). Prenatal DHA supply has a long term eect on
serotonergic and dopaminergic neurotransmission (Anderson et al.,
2005;Chalon, 2006) indicating the importance of DHA as a nutrient in
early brain development. DHA inuences gene expression, neuro-
transmission, and oxidative stress (Innis, 2018). DHA is an essential
factor for neurogenesis, phospholipid synthesis, and turnover (Coti
Bertrand et al., 2006;Kawakita et al., 2006;Salem et al., 2001).
The brain is atrophied in dierent neurodegenerative diseases.
Brain atrophy is also associated with age and cognitive degradation.
Various studies showed that DHA could improve learning and memory,
along with neuronal loss reduction (Weiser et al., 2016). DHA accu-
mulates during intrauterine fetal brain growth and maintains its levels
lifelong (Carver et al., 2001). DHA accumulation in the fetal brain is
highest during the third trimester of pregnancy. DHA incorporation into
brain membrane in early life solely depends on its supply via the pla-
centa, breastfeeding, and endogenous LCPUFAs production (Duttaroy,
2016;Innis, 2008;Lauritzen et al., 2016). DHA has a signicant role in
both brain and retinal development (Authority, 2011;Lauritzen et al.,
2016). Since the brain has a critical developmental window in utero as
Fig. 1. DHA synthesis in the body.
The plant source provides us ALA is converted
to EPA and DHA. The desaturations and elon-
gations occur in the endoplasmic reticulum,
and the β-oxidation occurs in the peroxisome,
to where 24-carbon PUFA are transferred. The
animal source provides us with EPA and DHA
without the need of conversion process. The
enzyme delta 6 desaturase is required to begin
the conversion of ALA.
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
23
well as during the postnatal life, therefore, any perturbations such as
nutritional and environmental or postnatal nutrition would sig-
nicantly aect brain development. During critical periods of devel-
opment, any perturbation leads to profound and potentially irreversible
defects of brain maturation. A signicant linear relationship between
maternal DHA level and umbilical cord plasma phospholipid contents
are observed (Calder, 2016). Optimal placental growth and develop-
ment are crucial for the eective exchange of nutrients and waste
products between the mother and the fetus (Basak et al., 2013). The
growing fetus mostly depends on the placental supply of maternal DHA
due to its limited DHA synthetic capacity (Duttaroy, 2000). Aberrant
placental development with a deranged vasculature may inuence fetal
development and survival (Duttaroy, 2016). Recent studies suggested
that DHA has a role in early placentation processes along with the brain
and retinal development during the last trimester of pregnancy (Basak
et al., 2013;Duttaroy, 2000;Johnsen et al., 2011). Preferential transfer
of maternal DHA to the fetus during the last trimester of pregnancy was
suggested to be performed by the high-anity placental plasma mem-
brane fatty acid-binding protein (p-FABPpm) (Duttaroy, 2009).
Intracellular DHA is transported by FABPs (please see details on
FABP in the next section). DHA is the ligand for peroxisome pro-
liferator-activated receptor gamma (PPAR-γ), which is expressed in the
embryonic mouse brain and neural stem cells. The critical early brain
development regulator, PPAR-γheterodimerizes with the retinoid X
receptor (RXR) and regulates the transcription of target genes (Wada
et al., 2006). DHA is one of the key ligands for brain RXR (Lengqvist
et al., 2004). Along with retinoic acid receptor, RXR plays an important
role in embryonic neurogenesis, neuronal plasticity, and catecholami-
nergic neuron dierentiation. RXR is highly expressed in the hippo-
campus (Lengqvist et al., 2004;Rioux and Arnold, 2005). As a free
radical scavenger, DHA protects the developing brain from peroxidative
damages of lipid and protein (Cao et al., 2004;Green et al., 2001;
Okada et al., 1996).
5. Fatty acid transport and metabolism in the human brain
It is generally assumed that the transport of fatty acids to the tissues
occurs in the form of the non-esteried pool of fatty acids (FFAs) bound
to serum albumin. The plasma FFAs is transferred across the cell via
fatty acid membrane transporters (FAT, FABPpm. FATP) and cyto-
plasmic fatty acid-binding proteins (FABPs) (Duttaroy, 2009). Fig. 2
summarises the putative roles of fatty acid-binding/transport proteins
in the uptake of free fatty acids. Recent studies showed that the
mammalian brain uniquely takes up DHA in the form of lysopho-
sphatidylcholine (LPC-DHA) (Chan et al., 2018). LPC-DHA uptake is
mediated by the major facilitator superfamily domain-containing pro-
tein 2 (Mfsd2 or Mfsd2a) present at the blood-brain barrier (Nguyen
et al., 2014). Therefore it may be necessary to increase the plasma level
of LPC-DHA for ecient enrichment of brain DHA in human, however
further work is required for conrmation. An essential requirement
common to both prenatal and postnatal brain development is the bio-
synthesis of a huge amount of membrane phospholipid, the origin of
which was believed to be exclusively derived from de novo biosynthesis
within cells of the brain, and acquisition of essential fatty acids from the
periphery into the developing brain. A major function of DHA during
brain development is to regulate SREBP-1 and SREBP-2 activity re-
sulting in major changes in phospholipid saturation(Huang et al.,
2017). FABP is thought to play a crucial role in the cytoplasmic fatty
acid transfer and thus help fatty acids aect gene expression and
synthesis of other metabolites. There are two types of FABPs available
in the brain: (1) B-FABP, which is found in ventricular germinal and
glial cells in the embryonic brain and in the astrocytes of developing
and adult brains and (2) H-FABP, which is only available in adult brains
(Owada et al., 2006;Veerkamp and Zimmerman, 2001). DHA has a
preference for binding with B-FABP that may be necessary for early
neurogenesis or neuronal migration (Owada et al., 2006).
Fatty acid metabolism is one of the vital steps for energy require-
ment in the brain. Brain gets 20% of total energy from β-oxidation of
fatty acid in mitochondria of astrocytes. In the pre-oxidation step, fatty
acids are initially converted to fatty acyl-CoA by acyl-CoA synthases.
Besides mitochondria, peroxisome also plays a signicant role in fatty
acid metabolism. Peroxisome proliferator-activated receptor α(PPAR-
α) stimulates the expression of catabolic enzymes, such as the CPT fa-
mily, and acyl-CoA dehydrogenases in low energy status (Tracey et al.,
2018). Through the β-oxidation, very long and branched-chain fatty
acids are oxidized to shorten them. Also, α-oxidation clears a single
carbon from fatty acids that are incapable of typical β-oxidation in
peroxisome (Tracey et al., 2018). The peroxisomal β-oxidation is unable
to breakdown the full fatty acids, while mitochondria degrade the fatty
acids completely via the tricarboxylic acid pathway (Tracey et al.,
2018). However, for energy production, utilization of fatty acids is in-
creased signicantly during fasting or extreme exertion which may
damage the brain due to reactive oxygen species, specically in the
form of superoxide (Tracey et al., 2018).
Another important pathway for the utilization of fatty acids in brain
astrocytes is the ketogenesis pathway. Ketone bodies may form from
fatty acid-derived acetyl-CoA in the hypoglycemic condition. In suitable
condition, these ketone bodies are lysed again into acetyl-CoA, which
again enter into the tricarboxylic acid cycle (Tracey et al., 2018).
6. Roles of DHA and its metabolites in brain function
As an integral component of cell membrane phospholipid, DHA
contributes to maintaining membrane uidity and lipid raft assembly
and other membrane functions. DHA inuences electrical, chemical,
hormonal, or antigenic signals of the cells. One study demonstrated that
higher signal transduction mediated by two DHA molecules than no or
one DHA molecule along with other highly unsaturated fatty acids in
the phospholipid bilayer (Calder, 2016). DHA acts via cell membrane
surface and intracellular receptors. DHA promotes membrane-asso-
ciated G-protein-coupled receptor (GPR)120 mediated gene activation
to promote anti-inammatory conditions (Oh et al., 2014). DHA also
activates PPARs and upregulates PPAR targeted genes to increase in-
sulin sensitivity, reduce plasma triglyceride level and inammation
(Calder, 2016). Dietary intervention plays a signicant role to maintain
healthy brain function, which prevents stress, depression, and brain
degenerative disorders (McEwen, 2010;Sun et al., 2018). The bene-
cial eects of DHA are mediated by the fatty acid itself (PPAR ligand)
as well as by its bioactive metabolites. DHA and its metabolites have a
wide range of actions at dierent levels and sites (Diep et al., 2000;
Zúñiga et al., 2011). The DHA metabolites have a wide range of actions
at dierent levels and sites. Table 1 summarizes various functions of
DHA metabolites. Bioactive DHA-derived specialized pro-resolving
mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX)
of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahex-
aenoyl amides of amino acids or neurotransmitters, and branched DHA
esters of hydroxy fatty acids are the metabolic end products of DHA
(Anderson and Taylor, 2012;Robertson et al., 2013). Also, epox-
ydocosapentaenoic acids (EDPs) and 22-hydroxydocosahexaenoic acids
(22-HDoHEs) are the metabolized from DHA (Kuda, 2017;Westphal
et al., 2011). 5-, 12- and 15-lipoxygenases (LOX), COX-2 and cyto-
chrome P450 (CYP) are the responsible enzymes for DHA metabolism.
Table 2 summarizes the enzymes responsible for DHA metabolism. As
most exigent by-products of DHA, resolvins are formed by either LOX15
or CYP or aspirin-treated COX-2 stimulation (Fig. 3)(Duvall and Levy,
2016;Sun et al., 2018). Although the LOX15 treated formed resolvins
are homologous to CYP, or aspirin-treated formed resolvins (Duvall and
Levy, 2016). As the potential inammation resolution mediators, re-
solvins act through a dierent GPR (Duvall and Levy, 2016;Serhan,
2014).
The neuroprotectors, resolvin D1, and aspirin-triggered resolvin D1
improve brain functions and impair neuronal death by downregulating
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
24
NF-kB, TLR4, CD200, and IL6R (Bisicchia et al., 2018;Recchiuti et al.,
2010). They induce remote functional recovery after brain damage
(Bisicchia et al., 2018). Resolvin D2 and aspirin-triggered resolvin D2
protect from cerebral ischemic injury through ERK1/2 phosphorylation
followed by stimulation of nNOS or eNOS to inhibit programmed
neuronal cell death and increase zonula occludens-1 for the main-
tenance of blood-brain barrier integrity (Zuo et al., 2018). Resolvin D3,
resolvin D5, aspirin-triggered resolvin D3, and aspirin-triggered re-
solvin D5 halt neuroinammatory process (Dalli et al., 2013;Hong
et al., 2005). However, the functions of other resolvins are still not
known.
Table 3 shows the DHA-derived resolvins and their receptors with
functions.
Macrophage derived anti-inammatory pro-resolving mediator;
maresins are biosynthesized from DHA in response to inammation,
healing, and regeneration process (Ariel and Serhan, 2012;Stables
et al., 2011;Zhang and Spite, 2012). Maresin 1(MaR1) is the leading
subtype of maresins. Along with the reduction of LTB
4
production,
MaR1 stimulates macrophagic phagocytosis and eerocytosis at the
inammatory site (Serhan et al., 2015b,2012;Serhan et al., 2008).
MaR1 regulates stem cell dierentiation to accelerate tissue repair
along with an analgesic role via TRPV1-mediated responses blockage
(Serhan et al., 2012;Yanes et al., 2010). MaR1 plays a role in the im-
provement of neurocognitive functions by regulating macrophage in-
ltration, NF-κB signaling, oxidative stress, and after cytokine release
Maresin 1 attenuates neuroinammation in a mouse model of perio-
perative neurocognitive disorders (Yang et al., 2019). Also, MaR1 has
shown signicant improvement of locomotive function in a post-spinal
cord injury model (Francos-Quijorna et al., 2017).
Neuroprotectin D1(NPD1) is one of the DHA derived SPMs, improve
brain cell survival, and repair in ageing and neurodegenerative diseases
(Bazan et al., 2011). Like MaR1, NPD1 also possesses anti-inammatory
and neuroprotective activity (Balas and Durand, 2016). However, NPD1
has anti-apoptotic activity, which makes it unique from MaR1 (Ariel
Fig. 2. Schematic representation of fatty acid transport mediated by fatty acid binding/transport proteins.
The family of FATPs, FAT, FABPpm and MFSD2A facilitate the uptake of fatty acids into tissues. However, the FATPs also possess ACSL activity and facilitate the ux
of fatty acids across membranes secondary to metabolic eects. After uptake, fatty acids are bound by cytoplasmic FABPs. Fatty acids can undergo a number of
metabolic fates. Fatty acid transport proteins modulate cognition by inuencing brain fatty acid transport and therefore by modulating the supply of the needed fatty
acids to the brain.
Table 1
Functions of DHA metabolites.
Types of metabolites Name of metabolites Eects
Oxygenated metabolites Maresins Resolution of inammation, wound healing, analgesic actions
Protectins Resolution of inammation, neuroprotection
Resolvins Resolution of inammation and wound healing
Electrophilic oxo-derivatives (EFOX) of DHA Anti-inammatory, anti-proliferative eects
Epoxides Anti-hypertensive, analgesic actions
Neuroprostanes Cardioprotection, wound healing
DHA conjugates Ethanolamines and glycerol esters Neural development, immunomodulation, metabolic eects
Branched fatty acid esters of hydroxy fatty acids (FAHFA) Immunomodulation, resolution of inammation
N-acyl amides Metabolic regulation, neuroprotection, neurotransmission
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
25
et al., 2005;Serhan et al., 2015b). In response to neuroinammation,
NPD1 is produced from endogenous DHA in retina and brain (Bazan,
2005;Calandria et al., 2009). Besides antiviral protection, NPD1 helps
in neurocognitive functions (García-Sastre, 2013;Morita et al., 2013;
Zhao et al., 2011). NDP1 can repress inammation, oxidative stress,
and cell apoptosis induced by Ab 42 and promote neuronal survival.
NDP1 may prevent Alzheimer's disease progression through upregu-
lating PPARγ, amyloid precursor protein-α, and downregulating β-
amyloid precursor protein. Thus, the amyloid-βpeptide is reduced in
neuronal tissue (Zhao et al., 2011).
Anti-inammatory signaling properties of EFOX and neuroprostanes
are benecial for dierent neuroinammatory disorders in association
with Parkinsons disease, and Alzheimers disease (Dyall, 2015;Gladine
et al., 2014;Groeger et al., 2010). On the other hand, docosahexaenoyl
ethanolamide improves energy homoeostasis in association with mood,
pain modulation, anti-inammation, hunger, and glucose uptake in the
brain through the endocannabinoid system (De Petrocellis et al., 1999;
Kim et al., 2014;Piazza et al., 2007;Soderstrom, 2004;Valenti et al.,
2005;Watanabe et al., 2003).
DHA glyceryl ester controls food intake and neuroinammation in
the brain in the same fashion as docosahexaenoyl ethanolamide by
using the endocannabinoid system (DAddario et al., 2014;Masoodi
et al., 2015). As an integral part of brain structure, the endocannabinoid
system has a signicant role in memory, cognition, and pain perception
(Wagner and Alger, 1996;Wilson and Nicoll, 2002). DHA conjugates
reduce neuroinammation and cause neurogenesis by acting on can-
nabinoid receptors (Calder, 2013;Lu and MacKie, 2016).
Stress-induced hormone production via hypothalamus-pituitary-
adrenal (HPA) axis pathways can be regulated and modulated by nu-
tritional approaches (Lupien et al., 2009;Ranabir and Reetu, 2011).
The lipid is an integrated part of the brain, so fatty acid status should
have a relationship with stress (Laugero et al., 2011;OBrien and
Sampson, 1965). Adequate dietary DHA supplementation lowers HPA
activation, corticosterone peak, and stress-induced weight loss (Chen
and Su, 2013;Hennebelle et al., 2012). Not only to alleviate short-term
stress, but DHA also has a signicant role in brain development, which
prevents anxiety and stress in later life (Robertson et al., 2013;Song
et al., 2008). Although, due to some conicting precedents for asso-
ciation with PUFA supplementation and cognitive development, it has
become more critical to determine optimum DHA doses for eective
neurodevelopment at dierent ages (Qawasmi et al., 2012;Simmer
et al., 2011;Smithers et al., 2008). Stress stimulated TNF-alfa, and IFN-
γproduction, lipopolysaccharide (LPS) stimulated IL-6 production are
reduced by a signicantly higher level of DHA supplementation
Table 2
Enzymes responsible for DHA metabolism.
Enzymes Mode of action
5-, 12- and 15-lipoxygenases converts DHA to DHA hydroperoxides (HpDHA), which are further metabolized by hydrolases, and several members of the CYP superfamily
(Serhan et al., 2015b;Spite et al., 2014).
Cyclooxygenase-2 converts DHAinto resolvins when triggered with aspirin, EFOX (Groeger et al., 2010;Lima-Garcia et al., 2011).
CYP Epoxygenases such as CYP2C, CYP2J produce EDPs from DHA, while ω/(ω-1)-hydroxylases such as CYP4A, CYP4F produce 22-HDoHEs (Westphal
et al., 2011).
Fig. 3. DHA metabolites formation and function in the brain.
DHA is converted into maresin 1(MaR1), neuroprotectin D1(NPD1) and resolvins by human 12-LOX, 15-LOX and CYP or aspirin-treated COX-2 enzymatically. These
metabolites have multiple functions in the brain, which have been mentioned in the upper and lower boxes. DHA is metabolised by P450 system, cyclooxygenase, and
lipoxygenase enzymes under dierent metabolic conditions.
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
26
(Kiecolt-Glaser et al., 2011;Lucas et al., 2009;Maes et al., 2000;
Robertson et al., 2013).
Though stress and anxiety have a close relationship with depression,
DHA is suggested to be an important nutrient for preventing and
treating depression (Murray and Lopez, 1996;Robertson et al., 2013).
DHA has shown some benecial eects in the treatment of various
psychiatric disorders, e.g., schizophrenia, unipolar and bipolar mood
disorders, anxiety disorders, obsessive-compulsive disorder, ADHD,
autism, aggression, hostility and impulsivity, borderline personality
disorder, substance abuse and anorexia nervosa (Bozzatello et al., 2016;
Sun et al., 2018). During the last decades several trials using n-3
LCPUFAs in mental diseases were performed. However, the ndings of
most of the trials are controversial and inconclusive(Pusceddu et al.,
2016;Sun et al., 2018).
There is evidence that consumption of n-3 fatty acids containing
shes reduce depression (Hibbeln, 1998). However, the studies have
shown that EPA is more potent to treat depression than DHA (Bourre,
2005;Marangell et al., 2003;Peet and Horrobin, 2002). Lower pro-
inammatory plasma IL-6 level and higher EPA/AA ratio have been
observed in PUFA treated depressed patients (Lin and Su, 2007).
Higher consumption of marine sh improves cognitive function
(Van Gelder et al., 2007). DHA has a signicant role in the reduction of
dementia risk (Schaefer et al., 2006). Neuroinammation can be dam-
pened by DHA supplementation in the pathogenesis of Alzheimers
disease (Kinney et al., 2018;Trépanier et al., 2016). DHA derived anti-
inammatory eicosanoids, neuroprotectins prevent Alzheimer's disease
pathogenesis (Lukiw et al., 2005). DHA regulates Alzheimer's disease-
related processes such as cholesterol and apolipoprotein E (APOE)
along with lipid raft assembly alteration and cell signalling regulation
(Boudrault et al., 2009;Hashimoto et al., 2005). Neuronal protection
against cytotoxicity, inhibition of nitrogen oxide production, calcium
inux, activation of antioxidant enzymes (glutathione peroxidase and
glutathione reductase) and reduction of apoptosis are the signicant
molecular functions of DHA (Seidl et al., 2014). The second most pre-
valent neurodegenerative disease, Parkinsonsdisease is suggested to be
prevented by the neuroprotective role of DHA (Seidl et al., 2014). At-
tention decit hyperactivity disorder (ADHD) is another common
neurodevelopmental disorder among school-aged children that leads to
severe problems in social behavior. Studies showed evidence for the
successful treatment of a mild form of ADHD symptoms with DHA
supplementation (Kiliaan and Königs, 2016). Several reviews on DHA
supplementation in ADHD were published in recent years(Ramalho
et al., 2018;Sun et al., 2018). Despite the heterogeneity of the studies,
DHA may contribute to improvements in the capacity of reading,
learning, nonverbal cognitive development, perceptive visual capacity
and executive function of ADHD children. Future in depth large-scale,
well-designed randomized clinical trials are required to achieve
evidence for clinical recommendations.
Bipolar disorder of the brain is characterized by periods of depres-
sion and mania. DHA improves depressive symptoms of bipolar dis-
order by increasing N-acetyl-aspartate levels in the brain, but it has no
signicant eects on the protection of mania (Bozzatello et al., 2016).
Intelligence quotient in children and cognitive function in the ageing
brain are improved by DHA supplementation (Lauritzen et al., 2016;
Weiser et al., 2016). Sun et al. (Sun et al., 2018)recently reviewed the
mechanistic relationships of brain DHA with dierent mental disorders,
including autism. Interestingly the studies have been reported that EPA
in association with DHA improves outcome in cognitive function than
DHA alone. DHA can be divided into two dierent types based on their
properties in brain function: lipid-bound DHA in membrane bilayer and
unesteried DHA (Innis, 2018). Lipid-bound DHA inuences lipid
rafting, signal transduction, and neurotransmission (Chalon, 2006;
Grosseld et al., 2006;Stillwell et al., 2005). On the other hand, reg-
ulation of gene expression and ion channel activities are related to
unesteried DHA properties (Bazan, 2006;Kitajka et al., 2002;
Vreugdenhil et al., 2002). DHA also inhibits cell migration, growth
arrest and apoptosis of brain tumor cells via activation of PPAR-γin the
nucleus (Mita et al., 2010).
7. DHA deciency and human brain function
As an integral component of brain structure, fatty acids play a sig-
nicant role in healthy brain function. Dierent diseases/disorders,
e.g., Alzheimer's disease, Parkinsons disease, Huntingtons disease,
schizophrenia, mood disorders, are linked due to altered membrane
fatty acid composition and their signalling in disease progression
(Bazinet and Layé, 2014;Shamim et al., 2018). The encephalopathy
Reye syndromeis causally associated with altered fatty acid oxidation
(Orlowski, 1999). A rare congenital peroxisome biogenesis disorder
called by "Zellweger syndrome," is linked with abnormal fatty acid
accumulation that impairs brain development (Crane, 2014). DHA de-
ciency is linked with depressive disorder, bipolar disorder
(McNamara, 2010;McNamara et al., 2007).
The studies on pregnant women showed that DHA deciency might
lead to poor language skill among children (Mulder et al., 2014). Even
autistic spectrum disorder or ADHD among teenagers is related to DHA
deciency (Bos et al., 2015;Parellada et al., 2017). Due to DHA de-
ciency, neurocognitive functional insuciency in young adults or
loneliness related memory problems in middle age has been observed
(Bauer et al., 2014;Jaremka et al., 2014). DHA deciency in the third
trimester signicantly aects brain development (Smith and Rouse,
2017).
Table 3
DHA-derived resolvins and their receptors with functions.
DHA-derived Resolvins Receptors Functions
Resolvin D1 Stimulates GPR32 and FPR2 (Serhan et al., 2015a)
Inhibits TRPV3, TRPV4 and TRPA1 (Serhan et al., 2015a)
Anti-inammatory (Qu et al., 2015)
Analgesic (Farooqui, 2012)
Resolvin D2 Stimulates GPR32, GRP18 and FPR2 (Lim et al., 2015;Shinohara and Serhan, 2016)
Inhibits TRPV1 and TRPA1 (Lim et al., 2015;Shinohara and Serhan, 2016)
Anti-inammatory (Qu et al., 2015)
Analgesic (Klein et al., 2014)
Resolvin D3 Stimulates GPR32 (Serhan et al., 2015a)Anti-inammatory (Qu et al., 2015)
Resolvin D4 Unknown Unknown
Resolvin D5 Stimulates GPR32 Anti-inammatory (Qu et al., 2015)
Resolvin D6 Unknown Unknown
Aspirin triggered resolvin D1 Stimulates GPR32 and FPR2 (Lim et al., 2015;Serhan et al., 2015a) Inhibits TRPV3, TRPV4 and
TNFR (Lim et al., 2015;Serhan et al., 2015a)
Anti-inammatory (Qu et al., 2015)
Analgesic (Farooqui, 2012)
Aspirin triggered resolvin D2 Unknown Unknown
Aspirin triggered resolvin D3 Stimulates GPR32 (Serhan et al., 2015a)Anti-inammatory (Qu et al., 2015)
Aspirin triggered resolvin D4 Unknown Unknown
Aspirin triggered resolvin D5 Unknown Unknown
Aspirin triggered resolvin D6 Unknown Unknown
R. Mallick, et al. International Journal of Developmental Neuroscience 79 (2019) 21–31
27
8. Clinical trials of DHA supplementation and brain function
N-3 LCPUFAs supplementation is recommended worldwide for feto-
maternal and maternal-childhood growth and development, and cog-
nitive function of the child(Carlson et al., 2013;Julvez et al., 2016;
Koletzko et al., 2007;Parra-Cabrera et al., 2011). DHA supplementation
improved pregnancy outcome, gestation, reduction in early preterm
and very low birth weight, childhood visual and psychomotor devel-
opment (Carlson et al., 2013;Shulkin et al., 2018).
Several clinical studies were reported on n-3 LCPUFAs and mental
disorders. Some of these clinical trials and their health outcomes are
presented in Table 4. Most of the clinical studies did not show any
signicant eects of DHA supplementation (Sun et al., 2018). Dier-
ences in methodologies, the sample size, dietary habit, selection cri-
teria, age, choice and dosage of LCPUFAs (EPA, or DHA, or a combi-
nation of EPA + DHA) and the duration of the intervention are mostl
possibly responsible for inconclusive results(Sun et al., 2018).
9. Conclusions
The optimal structure and function of the brain are critical for
quality of life, productivity and individual growth. DHA and its meta-
bolites inuence the brains development, structure and functions,
signaling pathways, receptor function, and enzyme activities. All these
functionalities are critical for optimum brain physiology throughout the
lifespan. In order to achieve these functionalities, sustained supply of
DHA is required well before conception, during the gestation period,
adolescence, adulthood and adult life. Therefore, maintaining optimal
levels of DHA in the brain are likely to be required throughout the
lifespan by obtaining preformed DHA via dietary or supplementation.
Several studies suggest that the consumption of DHA leads to many
inherent positive physiological and behavioral eects, however further
clinical trials are required to assess dierent clinical outcomes, in-
cluding mental health status and quality of life.
Declaration of Competing Interest
The authors declare no conict of interest.
Acknowledgements
This study was supported by the Throne Holst Foundation and the
Faculty of Medicine, University of Oslo, Norway.
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Table 4
Various clinical studies of DHA supplementation in relation with brain function.
Study Experimental setting Observed outcome
The Kansas University DHA outcome study (KUDOS) Cognitive and behavioral development Improvement of visual attention among infants has been observed
with the reduction of preterm birth risk (Colombo et al., 2019).
DHA supplementation on developmental outcomes of
toddlers born preterm
Developmental outcomes of toddlers Daily supplementation of DHA didnt improve cognitive function and
negative eects on language development in certain subgroups of
children (Keim et al., 2018).
Eect of DHA supplementation during pregnancy on
maternal depression and neurodevelopment of young
children
Neurodevelopmental outcome of children No reduction in postpartum depression in mothers nor improved
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Neurodevelopmental outcomes of preterm infants fed high-
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Neurodevelopment at 18 months age. Did not increase Bayley mental development index scores of preterm
infants overall born earlier than 33 weeks, but improved the Bayley
mental development index scores of girls (Makrides et al., 2009)
Neurodevelopmental outcomes at 7 years' corrected age in
preterm infants who were fed high-dose DHA to term
equivalent
Cognitive outcome detected at 18 months
age
Did not show any evidence of benet (Collins et al., 2015).
Feeding preterm infants milk with a higher dose of DHA
than that used in current practice
Language or behavior in early childhood. Did not result in any clinically meaningful change to language
development or behavior when assessed in early childhood (Smithers
et al., 2008).
DHA supplementation in children with ADHD DHA supplementation for 4 months
decreases the symptoms or not
No statistically signicant improvement of ADHD symptoms(Voigt
et al., 2001)
Maternal consumption of a DHA-containing functional food
during pregnancy: memory tasks at age 9 months
Problem-solving abilities and recognition
memory
Enhancement of problem-solving
skills but not recognition skills
at 9 months of age of infants(Judge et al., 2007)
DHA supplementation slows cognitive decline in Alzheimer
disease or not
DHA supplementation in individuals with
mild to moderate Alzheimer disease
DHA supplementation led to no benecial
eect on rate of cognitive and functional
decline (Quinn et al., 2010a).
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