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Omega-3 Fatty Acids and their Role in Central Nervous System - A Review



Polyunsaturated fatty acids (PUFAs) are crucial for our health and wellbeing; therefore, they have been widely investigated for their roles in maintaining human health and in disease treatment. Most Western diets include significant amount of saturated and omega-6 fatty acids and insufficient quantity of omega-3; however, the balance between omega-6 and omega-3 PUFA, in particular, is essential for the formation of pro- and anti-inflammatory lipids to promote health and prevent disease. As our daily diet affects our health, this paper draws attention to unique representatives of the omega-3 fatty acid group: alpha-linolenic acid and its derivatives. Recently, this has been shown to be effective in treating and preventing various diseases. It has been confirmed that omega-3 PUFAs may act as therapeutic agents as well and their significant role against inflammatory diseases, such as cardiovascular and neurodegenerative diseases, has been described. Some of nutritional factors have been described as a significant modifiers, which can influence brain elasticity and thus, effect on central nervous system functioning. Therefore, appropriate dietary management appears to be a non-invasive and effective approach to counteract neurological and cognitive disorders.
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816 Current Medicinal Chemistry, 2016, 23, 816-831
Omega-3 Fatty Acids and their Role in Central Nervous System - A
Tomasz Wysoczański1, Ewa Sokoła-Wysoczańska2, Jolanta Pękala1,3,*,
Stanisław Lochyński3,4, Katarzyna Czyż5, Robert Bodkowski5, Grzegorz Herbinger1,
Bożena Patkowska-Sokoła5 and Tadeusz Librowski6*
1FLC Pharma Ltd., Muchoborska 18, 54-424 Wrocław, Poland; 2
Lumina Cordis Foundation, Szymanowskiego 2A, 51-609 Wrocław,
Poland; 3Department of Bioorganic Chemistry, Faculty of Chemistry,
Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-
370 Wrocław, Poland; 4Institute of Cosmetology, Wrocław College of
Physiotherapy, Kościuszki 4, 50-038 Wrocław, Poland; 5Institute of
Animal Breeding, Faculty of Biology and Animal Sciences, Wrocław
University of Environmental and Life Sciences, Chełmońskiego 38C,
51-630 Wrocław, Poland; 6Department of Radioligands, Collegium
Medicum, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland
Abstract: Polyunsaturated fatty acids (PUFAs) are crucial for our health and wellbeing; therefore, they have
been widely investigated for their roles in maintaining human health and in disease treatment. Most Western
diets include significant amount of saturated and omega-6 fatty acids and insufficient quantity of omega-3;
however, the balance between omega-6 and omega-3 PUFA, in particular, is essential for the formation of
pro- and anti-inflammatory lipids to promote health and prevent disease. As our daily diet affects our health,
this paper draws attention to unique representatives of the omega-3 fatty acid group: alpha-linolenic acid and
its derivatives. Recently, this has been shown to be effective in treating and preventing various diseases. It has
been confirmed that omega-3 PUFAs may act as therapeutic agents as well and their significant role against
inflammatory diseases, such as cardiovascular and neurodegenerative diseases, has been described. Some of
nutritional factors have been described as a significant modifiers, which can influence brain elasticity and
thus, effect on central nervous system functioning. Therefore, appropriate dietary management appears to be
a non-invasive and effective approach to counteract neurological and cognitive disorders.
Keywords: Alpha-linolenic acid, ALA, blood-brain barrier, central nervous system, essential fatty acids, linoleic
acid, polyunsaturated fatty acids.
The identification of the role of essential fatty acids
(EFAs) is one of the major outcomes of recent scien-
tific research in the field of neuroscience. The conse-
quences of presence and deficit of various fatty acids
have gained importance in a variety of disciplines, in-
cluding physiology, psychology, lipid biochemistry,
psychiatry, nutrition, and neurosciences in general.
*Address correspondence to these authors at the Department of
Bioorganic Chemistry, Faculty of Chemistry, Wrocław University
of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław,
Poland; Tel: +4871 3202400; Fax: +4871 3202427; E-mail: and Department of Radioligands, Colle-
gium Medicum, Jagiellonian University, Medyczna 9, 30-688
Kraków, Poland; Tel: +48126205530; Fax: +4812 6205552;
Therefore, the presence of lipids, and fatty acids ratios
in diets, has thereby become a key question [1]. High
concentration of these essential fatty acids is found in
the brain where they have effect on perceptive and in-
tellectual, as well as on social and communicative
functions, but also on basic processes of growth and
development. Previous studies confirmed that alpha-
linolenic acid and its omega-3 derivatives have a major
influence on our nervous system and their deficiency
includes growth retardation, loss of motor coordination,
tingling sensation in the limbs and extremities, vision
impairment, and behavioural changes [2-5]. Despite the
fact that it is common knowledge that food intake is an
essential component of life, it is nonetheless often not
fully appreciated, that to control and conquer the ef-
fects of neural damage we should deliver health-giving
1875-533X/16 $58.00+.00 © 2016 Bentham Science Publishers
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 817
dietary molecules via both nourishment and dietary
supplements. During the last decades, people have de-
parted from healthy diet, which contained well-
adjusted ratio of omega–6 and omega–3 fatty acid and
the change toward a noticeable and important decrease
of omega–3 intake has been reported. Furthermore, in
this respect, it has been clarified that the present com-
mon ‘Western diet’ should be perceived as diet defi-
cient in omega–3 [6]. This review article refers to sev-
eral significant research studies investigating direct
effects of omega-3 PUFAs on neurochemical signal-
ling, neuronal composition, as well as to the role of
PUFAs in the central nervous system (CNS).
A bad reputation of fats for causing weight gain
does not change a perception that fat is essential for
survival. Since the 1980s, many institutions and orga-
nizations have published recommendations regarding
fat intake. One of them, the Dietary Reference Intakes
(USDA), recommends that as many as 20 to 35 percent
of calories should come from fat. In addition, it has
been stated that this amount of fat is suggested for
normal growth and development, energy production,
absorbing fat-soluble vitamins (A, D, E, K) and caro-
tenoids, providing cushioning for the organs and main-
taining the structure and function of cell membranes [7-
Fig. (1) presents the four main types of fat: satu-
rated, trans, mono-unsaturated (MUFA), and PUFA.
Saturated fatty acids characterize without double bonds
between carbon atoms; therefore, they form stiff and
inflexible fragments or particles. However, MUFA
have a single double bond, while PUFAs contain more
than one carbon double bond. Unsaturated fatty acids
containing a double bond in the trans configuration
(so-called partially hydrogenated fats) can be generated
during the industrial processing of liquid vegetable oils.
Although, considering organic double bonds present in
nature, most of them represent naturally the cis con-
figuration. The cis formation has an influence on the
plasticity of the molecule, in particular on the area
around the double bond, what makes the whole mole-
cule flexible; thus, fatty acids in trans configuration are
inflexible like abovementioned saturated fats.
Polyunsaturated fatty acids contribute significantly
to optimal health and development of humans and other
animals, and are therefore referred to as essential fatty
acids. Thus, the term “essential” signifies the impor-
tance of these compounds, as they cannot be synthe-
sized in the body but must be obtained from dietary
supplements or foods. Alpha-linolenic acid from the
omega-3 (ω-3) fatty acid family and linoleic acid from
the omega-6 (ω-6) family represent two primary EFAs.
Chemical structure designates whether a fatty acid is an
omega-3 or an omega-6. Omega-3 and -6 fatty acids
characterize with a double bond at the third and the
sixth carbon atom, respectively.
Plants possess the ability to produce elementary -3
fatty acids, as well as synthesize -6 molecules. Ani-
mals are not able to do so, and therefore they are de-
pendent on the dietary intake of these fatty acids [11].
As such, linoleic acid (LA; omega-6; 6; 18:26), the
parent fatty acid of the omega-6 group, has to be pro-
vided to the organism. Each and every following fatty
acid from -6 fatty acid family is a derivative of LA.
Alpha-linolenic acid (α-linoleic acid, ALA, omega-3,
3, 18:33) is the precursor compound of the omega-3
group. Following compounds of the omega-3 group
represent derivatives of ALA, and together constitute
the PUFA. Desaturation and elongation are the two
crucial reactions, thus common mechanisms providing
conversion of the particles to longer chain fatty acids.
These processes are common because involved en-
zymes act similarly in the two fatty acid groups. There-
fore, we observed a competition for the same enzymes
by the omega-6 and omega-3 fatty acids (Fig. 2)
The differences between omega–6 and omega-3 ac-
ids seem to be minimal from a chemical point of view,
and could be seen as insignificant. These acids are re-
sponsible for diverse and in some cases even contrary
effects that are not clarify effortlessly. It has been sug-
gested that the distinction between omega-6 and
omega-3 PUFA occurs due to the differential capacity
of proteins in general, but also proteins bound in or by
membranes in particular, to distinguish numerous PU-
FAs [14,15]. The nutritional deficiency of omega-3
fatty acids and the specific and unique functions of
omega-6 and omega–3, have become the focus of nu-
merous research groups around the world. Deficit in
n6 LA results in poor growth, skin lesions and repro-
ductive and fatty liver failure [16-18]. The symptoms
of n-3 ALA deficiency are still much unknown and
have only been well examined in human infants and
experimental animals. Most omega-6 fatty acids facili-
tate inflammation. In contrast, omega-3 fatty acids help
in reducing inflammation. n-3 Fatty acid deficiency
causes reduced vision, and abnormal electroretinogram
results. Also, research involved studies on rodents have
818 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.
Fig. (1). Structures of common dietary fatty acids.
Fig. (2). Essential fatty acids and their derivatives.
reported significant impairment due to n-3 PUFA defi-
ciency on learning and memory, cognitive and behav-
ioural functioning [19,20].
The intake, absorption and breakdown of ALA in
human body have been characterized thoroughly. Once
ALA is absorbed, the organism transforms it to very-
long-chain PUFA: promptly to eicosapentaenoic acid
(EPA, 20:5n-3) and more slowly to docosahexaenoic
acid (DHA) (22:6n-3). The most important effect of
ALA deficit is that its principal end product, DHA, is
Stearic Acid C18:0
Elaidic Acid C18:1 (trans)
Oleic Acid C18:1 (cis)
Linoleic Acid C18:2
Linolenic Acid C18:3
Arachidonic Acid
Acid C22:6
Omega-6 fatty acid Omega-3 fatty acid
C18:2n-6 C18:3n-3
Formation of new double bond
LA – Linoleic Acid:
Corn oil
:ALA – -Linoleic Acid:
Flaxseed oil
Canola oil
Increase in chain length
C20:3n-6 C20:4n-3
Formation of new double bond
afflower oil
Sunflower oil
Soybean oil
C20:4n-6 C20:5n-3
Increase in chain length
AA – Arachidonic Acid: :EPA – Eicosapentaenoic Acid
Oily fish
Fish oil capsules
Docosahexaenoic Acid
n-6 PUFAs
Inflammation accentuation
n-6 PUFAs
Inflammation accentuation
n-3 PUFAs
Inflammation attenuation
n-3 PUFAs
Inflammation attenuation
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 819
not sufficiently synthesized [19]. DHA is a key mole-
cule of the brain and retina, building the neuronal
phospholipid membranes. Therefore, its deficiency in
these organs has been associated and consequently re-
sults in abnormal function. Moreover, omega-3 fatty
acid deficit is emphasized when there occurs a high
linoleic acid content in the diet at the same time, which
leads to inhibition of the synthesis of DHA from LA
[21]. Omega-6 LA is converted to arachidonic acid
(AA, 20:4n-6) through the steps outlined in the eicosa-
noid synthesis pathway. Dietary sources of the LA in-
clude vegetables and seed oils (e.g. from plants culti-
vated for oils: safflower, sunflower, and corn). First,
linoleic acid is converted to gamma-linolenic acid
(GLA, 18:3n-6). GLA itself can be ingested from sev-
eral plant-based oils including borage oil, and the acai
berry. Consequently, diets based on corn, sunflower,
and peanut oils, that constitute rich LA source and at
the same time contain very low ALA concentration (or
do not contain ALA whatsoever), lead to omega−3
fatty acid deficiency [22-24].
GLA is converted to dihomo-γ−linolenic acid
(DGLA) and later to arachidonic acid. As a result of its
transformation to obtain active compounds (prosta-
glandin PGF2alpha and PGE2) after workout and
physical exercise, AA is needed for the reparation and
skeletal muscle tissue growth [25]. The arachidonate-
derived eicosanoids take part in varied biochemical
processes and conditions (e.g. platelet and leukocyte
activation, gastric secretion regulation, initiation of
bronchoconstriction, and signalling of pain). These
mechanisms have created aims for pharmaceutical
companies and numerous pharmacological agents (leu-
kotriene antagonists, COX-2 inhibitors, and the non-
steroidal anti-inflammatory drugs).
Omega-3 PUFAs absorbed from diet conquer fever;
indicated pain and the inflammatory states induced by
omega-6 PUFAs activities, as they shift AA from cell
membranes. Moreover, PUFAs from omega-3 group
compete with the enzymes converting AA into the bio-
logical eicosanoids (TXs, LTs, and PGs). Increase of
omega-3 PUFAs dietary consumption relative to
omega-6 PUFAs should reduce the potential for neu-
trophils, eosinophils (i.e. leukocytes), and monocytes to
synthesize potent mediators of inflammation and to
reduce the ability of platelets to release TXA2 [26-29].
Other dietary sources of ALA include the vegetable
and seed oils (e.g. perilla, walnut, flax, canola, soy,
chia, pumpkin seed and hemp). ALA also occurs in
wild plants, for example purslane. Exposition of prod-
ucts that contain ALA to air, heat, or light can destroy
their nutrient value. Therefore, high-quality oil is bot-
tled in light-resistant containers and refrigerated. An
elevated proportion of n-6 to n-3 fatty acids in the in-
take emphasizes deficiency of n-3 fatty acid. Dietary
ALA is especially important for the nervous system,
inter alia, in the development of the brain and the ret-
ina [11,30]. Table 1 presents the ALA concentrations in
individual food items
All tissues of human body need to take in omega-3
and omega-6 fatty acids through cell membranes and
incorporate them into molecules with specific func-
tions, essential to the process we call life. However, a
significant effect of dietary modification of fatty acid
configuration is competition between omega-3 and
omega-6 PUFAs for incorporation into cell mem-
Table 1. Alpha-Linolenic a cid content of various oils
and common foods [23,31,32].
PRODUCT α-Linolenic acid, % by wt
KALE 0.13
Very early in prenatal life begins protracted process
of brain development. However it is said that this is
lifelong project, disruption at an early stage can cause
particularly harmful and long-lasting negative conse-
quences. Both brain development and brain function
require essential fatty acids. Although the brain is ma-
terially an organ like any other, to be exact developed
from matter coming from the diet, for a long time it
was not believed that nourishment could affect brain
820 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.
structure, and thus its function. The effect of diet (nu-
trients) on the composition, organization and activities
of the brain was very well demonstrated especially by
omega-3 fatty acids. The human brain constitutes one
of the richest organs in lipid content, and the only role
of lipid molecules is to form fundamental membrane
structure. The human brain consists in 60% of fat; more
than half of the dry weight of our brain includes phos-
pholipids, mainly glycerophospholipids and sphin-
golipids. One third of these are essential fatty acids. In
the brain, the ratio of omega-3 to omega-6 is 1:1. The
fatty acid distribution is the brain is tissue-specific,
with a predominance of MUFA at the level of the white
matter and a majority of PUFA in the grey matter.
Polyunsaturated fatty acids are divided into two sets:
the omega-6, with arachidonic acid (AA, 20:4) as the
main representative in the brain tissue; and the omega-
3, with the prevalence of docosahexaenoic acid (DHA,
22:6) at the level of the CNS membranes. The amount
of DHA exceeds that of AA in the grey matter, while in
the white matter the ratio is reversed [33-38].
During postnatal development, DHA in the brain
takes over; the ALA, which is taken with the diet, is
initially recruited by the liver in which it first under-
goes the action of desaturase and elongase enzymes for
the synthesis of omega-3 fatty acids, and then it circu-
lates in the blood stream to reach the CNS.
Feeding rats with diets containing oils with a low
ALA concentration (e.g. sunflower oil) effects in de-
creased DHA level in all brain cells and tissues, when
related to animals eating a food supplemented with
soybean oil or rapeseed oil rich in ALA. The ALA-
deprived diet results in abnormalities in the electroreti-
nogram; this effect wanes with age. Low effect on mo-
tor activity has been found, but ALA-deprived nutrition
shows critical influence on learning tasks (estimated by
application of the shuttle box test). Feeding rats with a
diet low in ALA demonstrate an earlier mortality in a
study with an intraperitoneal neurotoxin injection
(triethyltin) compared to animals supplemented with a
common soybean oil diet [39].
Rat brains with induced essential fatty acid defi-
ciency have been used as an animal model in many
various studies [40-43]. Induced changes in fatty acid
composition of rat brains have been applied to examine
alterations in volatile anesthetic potency. Moreover, in
an attempt to gain greater insight into molecular
mechanisms of anesthetic action, a dietary approach to
manipulate the fatty acid component of rat brain phos-
pholipids has been utilized. The area of anesthetics is
of particular interest to researchers, as Lochynski and
coworkers have been investigating the synthesis of
various anesthetic compounds and studying their influ-
ence on phospholipid bilayers using molecular dynam-
ics as well [44-47]. In the above cited research, rats fed
a fat-free diet demonstrated a substantial reduction of
AA (omega-6) and DHA (omega-3) in the brain, and
also omega-9 Mead acid increased level was also
found. The rats described as a fat-deprived have been
considerably more sensitive to all of studied volatile
anesthetics when compared to age-controlled animals
fed a standard nutrition. Furthermore, supplementation
with ALA (omega-3) via enriched diet to the fat-
deprived animals rebuilt entirely the level of DHA in
the brain, leaving anesthetic sensitivity unaffected.
Quite the reverse, administration of LA (omega-6) re-
sulted in a significant reduction in anesthetic vulner-
ability; however, in regard to arachidonate concentra-
tion no more than a minor alteration in whole brain was
observed [48]. As a consequence, this study also initi-
ated the following examination for defining whether
essential fatty acid deficiency is able to modify the
generation of chemical second messengers. The results
of this research describe the characteristic modifica-
tions in phosphoinositide mass and arrangement of
fatty acids detected in brains with essential fatty acid
deficit [49].
Studies reported that proper functioning of brain
cells and correctness of the differentiation progression
of cultured neurons require both ALA and also some of
omega-3 and omega-6 molecules, characterized by ex-
tended carbon chains. Furthermore, ALA deficiency
modifies brain process of development, disturbs the
structural components of brain, related to both physical
and chemical properties (e.g. cell membranes, oli-
godendrocytes, neurons, and astrocytes). Such modifi-
cations result in physicochemical changes and induce
physiological and biochemical disturbances [39,50].
Omega-6 and omega-3 compete for the same en-
zymes, which are commonly involved in their biosyn-
thesis (e.g. desaturase). As a consequence, excessive
omega-6 intake can affect omega-3 formation originat-
ing from ALA. Not surprisingly, in Western countries
the typical diet presents an omega-6/omega-3 ratio of
about 10:1, while the optimal ratio should be 4(5):1.
Each tissue has a characteristic composition of fatty
acids, which ensures its identity. Regarding the nervous
tissue, the ratio is about 2:1 and its imbalance results in
significant alterations in the neuronal membrane, with
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 821
considerable consequences for the functioning of the
nervous system.
A disproportional omega-6/omega-3 ratio may alter
the structural properties of the neuronal membrane,
which strongly influences the properties of the neurons
themselves. In general, PUFA reduce the excess of
cholesterol within the membranes, thus avoiding dele-
terious membrane rigidity [51]. Clinical studies report
that a proper intake of omega-3 PUFA improves cogni-
tive performance by increasing the acetylcholine levels
in the hippocampus, the production of anti-
inflammatory molecules, and the increment of neuro-
plasticity. It has been also demonstrated that a defi-
ciency of DHA content in the brain tissue might influ-
ence on the activity of enzymes that are associated with
the plasma membrane, ion channels, and receptors
which are related to signal transduction [34,36,50].
The blood–brain barrier (BBB) characterizes with
high selectiveness of penetrability that function by
separating the circulatory blood from the brain ex-
tracellular fluid in the CNS. The BBB is consisted of
capillary endothelial cells. It allows the passage of cer-
tain gaseous substances, water, as well as lipid soluble
particles by the way of passive diffusion. In addition, in
case of e.g. glucose and amino acids, BBB enables the
selective transfer of compounds. Increasing experimen-
tal and clinical evidence indicates that the BBB is get-
ting attention as a feature in common neurologic disor-
ders (e.g. epilepsy, stroke, schizophrenia and traumatic
brain injury [52,53].
A comprehensive summary on the subject of the
complicated machinery of transport the essential PUFA
as it progresses from the blood into the brain was pro-
vided by Rapoport et al. They discussed the effects of
dietary supplements in the context of tool for treatment
of states of PUFA imbalance. Also, in their work, it has
been reported that organizational modifications occur
in the BBB complex in the elderly, as well as in Alz-
heimer patients [38]. Unfortunately, our understanding
of functional alterations is relatively limited. The ma-
jority of research has not found an evidence of the al-
tered permeation rate of PUFA throughout aging
[54,55]. Base on the obtained information, no differ-
ence was found among younger and older animals re-
garding the AA permeation into the brain. Although,
this observation confronts another original work which
has established a smaller amount of AA entered an
older brain tissue. Hence, without conclusive confirma-
tion, it was proposed the saturated FA, but not PUFA,
require a specific transporter to overcome and cross the
BBB, and that LA can restrain a passage of palmitic
acid (PA). PA then increases LA transition into the
brain [56,57]. Other studies have reported no alteration
in the PUFA transition ratio into an old brain; however,
these studies observed such a variance among the
young and old brain which was credited to the bio-
chemical mechanisms distinctive respectively these age
group. It has been observed on animals that a diet defi-
cient in ALA provokes some leaks in the BBB which is
interesting in terms of the transport of drugs, for in-
stance, which could be dramatic in terms of the trans-
port of toxins [58,59].
Saturated fatty acids (SFA) represent another lipid
class that is able to influence the integrity of the nerv-
ous tissue with its structure. SFA are constituted by a
carbon chain characterized only by single C-C bonds.
These lipid molecules are embedded within phosphol-
ipids and confer rigidity to the plasma membrane; thus,
proper nutrition is required in order to balance their
Loss of BBB functions may appear as a result of
disturbances in cerebral capillary integrity, and thus be
triggered as a consequence of disorders motivated by
neurovascular degenerations, which have been con-
nected with chronic systemic inflammation state. It has
already been demonstrated how an SFA excess is con-
nected with the onset of several pathologies, such as
cardiovascular diseases, dyslipidemia, and metabolic
syndrome. Several studies have also shown how these
diseases are associated with an enhanced risk of devel-
oping neurodegenerative diseases (e.g. Alzheimer's
disease) [60-62]. Another studies also indicate that
regular consumption of SFAs, TFAs, and cholesterol, is
positively and synergistically connected with increased
risk of AD, through mechanisms that include endothe-
lial dysfunction, inflammation, oxidative stress, and
dyslipidemia [63].
Furthermore, a diet rich in SFAs, TFAs, and choles-
terol can favourable condition for the onset of nervous
system disorders by affecting the vascular integrity. In
neurodegenerative diseases, the expression of symp-
toms is preceded by a dysfunction of brain capillaries
and a reduction of tight junctions with subsequent ex-
travasation of plasma proteins, including antibodies,
within the brain parenchyma. In this way, astrocytes
are activated creating a barrier between the endothelial
cells of the BBB and neurons. When damage to the
822 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.
nervous tissue is present, these cells are activated and
converted into macrophages, which are able to clean
the tissues through phagocytosis and by producing cy-
tokines and other pro-inflammatory factors. By regulat-
ing the dietary intake of fatty acids, it is possible to re-
duce the inflammatory process on which BBB integrity
and, consequently, the entire nervous system function-
ality depend [64-66].
The aging process and systemic changes induced by
it have a substantial impact on the brain; moreover,
process of brain aging is very complex and including
many independent and inter-related factors. An aging
brain is connected with countless physiological, chemi-
cal, biological as well as behavioural shortages (e.g.
pain threshold alteration, sleep disturbance, learning
and memory loss, and disturbed thermoregulation)
The structural approach has been proposed to un-
derstand the aging process (i.e. key structural modifica-
tions appearing throughout the progression) at all levels
(molecules to morphology). In addition, the composi-
tion of PUFA in the brain tissue is age-specific. Al-
though, the alteration course and direction of change,
still have not been confirmed. It is obvious that study
of elongated and deliberate ageing requires a statistical
model; however, there is no statistical pattern that
could help to foretell either the degree or form of the
structure or functioning degeneration. Throughout the
process, for incomprehensible reasons the brain tissue
capability to form novel synapses (synaptogenesis) is
reduced. Simultaneously, key changes based on bio-
chemical matter are occurring in the brain which can
perturb the membrane of the neurons — a place where
functions like the transmission of neuronal signalling
along the axon, control of the structure and activity of
ionic channels, regulation of membrane bound en-
zymes, and sustainment of numerous receptor groups
are happening. Throughout aging, an increase in the
cholesterol concentration in the neuronal membranes
and the toxic metabolites of cholesterol (24-OH-
cholesterol) is observed. Also, the correlated firmness
of the neurons membrane has been notably raised. The
structure of neuronal membrane is responsible for typi-
cal and regular function on physiological basis, but
whereas a lot of factors have been associated with af-
fecting membrane flexibility, the arrangement of lipids
is one of the main determinants. It has been precisely
described how cholesterol degrades flexibility of the
membrane, while polyunsaturated fatty acids show op-
posite effect. LC-PUFA (long chain polyunsaturated
fatty acid) can be directly delivered to the brain from
the dietary sources, or by additional supplementation of
essential fatty acids (LA and ALA) brain is able to
transfigure them to LC-FA [6,69].
Several clinical studies have shown how the omega-
6/omega-3 ratio was dependent on time: during the
normal aging process, phospholipids of the cerebral
cortex undergo a progressive increase in the levels of
DHA with a consequent decrease in AA, while in in-
fants the DHA/AA ratio is close to 1 [70]. The LA lev-
els increase strongly with age, suggesting a loss of effi-
ciency of the desaturase enzymes, which are responsi-
ble for the enzymatic transformations.
An increase in cholesterol levels results in certain
efficient alterations occurring in BBB. Research con-
ducted in that matter have shown how normal fatty ac-
ids biochemical mechanisms malfunction in the brain
that undergo aging process (e.g. fatty acid assimilation
into the membrane is reduced as well as the transition
level is slowed down) [71]. Also, a decrease in the ac-
tivity level of the desaturase enzymes (e.g. delta-9) and
other elongating enzymes is observed [72]. The pas-
sageway to phospholipids formation is also blocked
[73]. Generally, while these combined different actions
interact together, it leads to a decline of membrane
flexibility index. It is worth mentioning here that MRI
studies of human brain tissue have approved previous
findings that omega-3 PUFA can prevent the brain tis-
sue from negative influence of aging processes. Also,
other experimental data have clarified the involvement
of omega-3 PUFA in neuroprotection, neurogenesis,
and neurotransmission thus supporting the brain in cop-
ing with aging [74].
Many attempts have been made to gain and present
a complete understanding of the determinants responsi-
ble for neuronal membrane rigidity. For example, the
fact that the summarized PUFAs concentration de-
crease in the elderly might be associated with de-
creased passing level through the BBB or a higher fre-
quency of assimilation into the membrane. Earliest re-
search has reported dietary application of a specific
combination proportion of omega3/omega-6 PUFA
resulted in numerous various benefits (e.g. a decreased
cholesterol level as well as an increased content of
PUFA in the neurones membrane) [75]. Yehuda also
reported that the ratio of 1:4 of omega3/omega-6 PUFA
is able to block or even restore diversified undesirable
previously-mentioned effects correlating with aging
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 823
The lipid content and arrangement in the membrane
influences its fluidity. The lipid element is character-
ized by a high turnover status as opposed to the protein
part that is more firm and fixed. Both the transition
temperature (i.e. the condition at which cell membrane
is changing from one state to another; in this case con-
verts from fluid to gel-like state) as well as tight and
dense packing can control the membrane fluidity. Pres-
ence of unsaturated fatty acids lowers the transition
(melting) temperature; cholesterol, in addition, sup-
presses the trigger transition temperature and also dis-
rupts packing by cell membrane insertion. The critical
melting temperature might alter along with aging proc-
ess, simultaneously with the cholesterol accumulation.
Parameters of membrane flexibility may also be con-
trolled by the neuron cells in multiple methods, i.e. de-
saturation of fatty acids; transfer of fatty acids between
molecules; enhanced production of unsaturated fatty
acids, together with changes in length of phospholipid
tail [76].
PUFAs particles responsibility focuses above all on
controlling and normalizing cellular differentiation and
apoptosis. Research conducted on aging reported a ma-
jor reduction in the content and PUFAs turnover status
(e.g. in the cortex, hypothalamus, hippocampus, and
striatum). A significant alteration in the melting tem-
perature, a modification that leads to increased rigidity
of the membrane is observed during ageing; conse-
quently, the variation is more intense in Alzheimer's
patients. In this respect, DHA (docasahexanoic) and the
AA (arachidonic) acids represent the most studied fatty
acids. In aging rats, the DHA and AA content is de-
pleted in neuronal membrane of elder hippocampus.
Therapy based on omega-3 fatty acids supplementation
enhances and improves the membrane condition. Ulti-
mately, there is more than one explanation for the re-
duced status of PUFA in the aging brain. One of them
is the depleted level of PUFA passage from the circu-
lating blood into the brain. The other one is disordered
biochemical mechanism that would be predicted to
embed and lengthen the fatty acid chain. Both indicated
options are straightway associated with their individual
primary matters: the issue of the blood-brain barrier
and the dynamic-changing aspects of fatty acid brain
metabolism [77-80].
Modifications in the composition of dietary fatty ac-
ids result in changes in the composition and function of
neuronal membranes. These changes are not only re-
lated with the physical and chemical properties of the
membrane (e.g. fluidity), but also with the effects that
diet has on the gene expression. Accordingly, the over-
expression of neuronal genes induced by DHA may
lead to improvements in brain function.
Nutritional regimen including PUFA-enrichment
leads to substantial alteration in the expression of cer-
tain genes in the central nervous system. The conse-
quences seem to be autonomous from induced effects
on membrane structure. PUFA can regulate the gene
expression via their ability to interact with specific or
non-specific ligands. These ligands attach to response
factor structures acting on cis-regulatory sites of the
gene that, in the end, activate or inactivate mRNA syn-
thesis. It can be mentioned as an example that PUFAs
are able to affect directly transcription factors, such as
peroxisome proliferator-activated receptors (PPAR),
which can modify the expression of target genes. To
understand fully positive and beneficial effect of
omega-3 on the central nervous system, direct conse-
quences of PUFA influence on transcriptional factors
seems to be crucial matter to comprehend. Further-
more, the subsequent developmentally and tissue-
specifically molecules triggered by gene expression
may also be a clue to recognition advantageous proper-
ties of omega-3 fatty acid group [81,82].
These observations suggested new avenues for fur-
ther studies, which have highlighted the positive effect
of omega-3 (both DHA and EPA, ALA derivatives) on
some neurological diseases such as schizophrenia, de-
mentia, as well as other central nervous system disor-
ders (e.g. depression). As a result, the omega-3 group
and especially the parent compound of the omega–3
group, ALA, have the ability to influence either cogni-
tive functions or mood and emotional states by acting
as a mood stabilizer.
It has been observed how dietary sources rich in
both omega-3 PUFA (ALA and DHA) and a combina-
tion of omega-3 and omega-6 PUFA undoubtedly af-
fect neural energy metabolism and ATP-generating
pathway. This observation was confirmed by signifi-
cantly up-regulated expression of four different
subunits of cytochrome c oxidase, cytochrome b, and
also ATP synthases. In some brain regions, normal
fatty acid composition is restored by supplementation
with phospholipids. Thus, positive effects of ALA and
DHA on memory, cognitive functions and learning
abilities have been confirmed both in animal and hu-
man tissues studied group [75,83,84].
824 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.
Current clinical studies have also explored a possi-
ble correlation between PUFAs and sleep quality, with
simultaneous estimation of vitamin D influence in that
matter. Vitamin D refers to a group of fat-soluble
secosteroids and their status has been highly associated
with a regulation of nervous system development and
function, and inflammation state as well [85-88].
Hansen et al designed a study to describe the rela-
tionship among levels of EPA and DHA, and their in-
fluence on sleep, daily functioning and vitamin D con-
centration. Motivated by former pilot experiment dem-
onstrating that ingesting fatty fish for a six months up-
graded level of vitamin D and improved heart rate vari-
ability in a samples of Norwegian prisoners although
they were exposed to limited daylight access. Recent
research involved male patients with sleep problems
from secure forensic facility in the USA divided into
test group - consuming salmon three times per week
and control group - receiving an alternative meal. Fatty
fish was applied as a main dietary source of vitamin D
and the marine omega-3 fatty acids: EPA and DHA.
Based on EPA and DHA level in red blood cells, con-
sumption of fish-enriched diet appeared to have a posi-
tive influence on sleep performance in general as well
as in particular on daily functioning. During both pre-
and post-intervention period male subjects were exam-
ined and their sleep latency, sleep efficiency, actual
sleep and actual wake time, and daily functioning were
assessed. Obtained results exposed substantial increase
in sleep latency from pre- to post-test in the control
group, however, the increase was not found in the fish
group. The study results showed that participants with
regularly fish intake had higher red blood cell concen-
trations of indicated omega-3s, increased serum vita-
min D levels and reported on an improved sleep qual-
ity, daily functioning and heart rate variability (HRV),
compared to the control group [89,90].
Another recent study involved preliminary school
children explored whether 16 weeks of daily 600mg
supplements of algal sources would improve their sleep
performance. The results of randomized placebo-
controlled research by the University of Oxford indi-
cated clearly that children receiving omega-3 supple-
ments slept an hour longer and much quieter than their
peers. A higher blood DHA concentration - the key
omega-3 fatty acid found in the brain - has been sig-
nificantly associated with superior sleep performance
with less bedtime resistance, parasomnias and total
sleep disturbance [91].
Study conducted by Burgess et al. by means of
plasma lipid contrast analysis revealed that patients
with lower total n-3 fatty acids contribution had been
significantly more often suffer from behavioral im-
pairment, temper tantrums, often linked with learning
and sleep difficulties when compared to subjects with
high proportions of n-3 fatty acids. It was signified that
future studies in this field should be held in order to
describe relation between PUFAs status and the behav-
ior problems exhibited by children, what seems to be
related, yet, remains unclear [92].
To date, the theory that low levels of significant
fatty acids in the blood causes sleep problems and cog-
nitive dysfunctions with difficulties in concentrating
has been often explored. Blood biochemical indication
has also suggested that a relative deficiency of particu-
lar polyunsaturated fatty acids may be inseparably re-
sponsible for some of the behavioral and learning dis-
orders crucial to attention deficit hyperactivity disorder
(ADHD). It has also been found that adults with
ADHD continue to exhibit abnormal EFA status that is
often detected in younger children [93,94].
Richardson et al. verified a common theory that
highly unsaturated fatty acids deficiencies may underlie
some of the behavioral and learning problems allied
with ADHD. A group of 41 children characterized by
defined learning problems and above-average ADHD
scores have been randomly assigned to PUFA supple-
mentation research group or placebo control group.
Diversified subscales were used to assess individual
features of ADHD e.g. Oppositional, Cognitive Prob-
lems, Hyperactivity, Anxious/Shy, Perfectionism, So-
cial Problems and Psychosomatic and also global scale
(among others Conners’ ADHD Index). Omega-3 and
omega-6 supplementation for 12 weeks under double-
blind conditions was found to benefit significantly bet-
ter than placebo in children with specific learning prob-
lems. Test treatment group demonstrated reduced rat-
ings for ADHD-related symptoms in comparison to
control group – children from research group present
significantly lower scores on accepted scales and sub-
scales (Psychosomatic, Cognitive Problems and Anx-
ious/Shy, Restless–Impulsive index). What turned up to
be particularly important among the placebo group,
there were no improvements on any established scale at
12th week in comparison with baseline results [95].
Although many publications indicate importance of
the subject and potential therapeutic benefits of PUFAs
supplementation, there is constant need for expanding
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 825
horizons of knowledge related to ADHD and cognitive
disorders treatment. Gillies et al., authors of review
paper pointed out that amount of evidence that PUFA
supplementation provides any profits is still insuffi-
cient. However, information from 2011 databases re-
viewed by authors suggested there was a significantly
higher probability of improvement in the group receiv-
ing omega-3/6 PUFA compared to placebo after sup-
plementation for a period of between four and 16
weeks [96-99].
In 2006 Joshi et al. published study based on 200
mg plant-based ALA administration in the form of
flaxseed oil with vitamin C to children with ADHD.
Increased concentration of circulating EPA and DHA
has been found together with reported improvement in
ADHD symptoms (e.g. self-control, restlessness, im-
pulsivity) rate by parents. However, dependence only
on parent description, absence of control group in the
research and simultaneous supplementation of vitamin
C hold off from drawing firm conclusions about the
independent effect of ALA [100]. Moreover, a research
describing specifically the effect of ALA daily supple-
mentation on ADHD indications in children (6-16
years) reported that no significant alterations were
found in any of the estimated variables tested before
and after supplementation, in both research subject
groups. However, authors described problems with de-
livery performance (capsule size) and the group size of
investigated children as well as control group were far
too small, thus not representative for this population
[101]. Hence, the presented research had some limita-
tions that should be noted. As published meta-analyses
and methodical reviews on this subject pointed out,
there is no steady consensus that omega-3 PUFAs im-
pact ADHD symptoms unequivocally [102,103].
Major depression is one of the most common mental
disorders diagnosed between people reached adult age
worldwide. The World Health Organization has listed
depression as one of the single most difficult and bur-
densome diseases worldwide based on years lived with
disability. Also, depression is characterized by high
index of lifelong predominance, outbreak at relatively
early age, and function loss. In the prevention of de-
pression, increasing attention has been paid to the role
of diet and nutrients as an etiologic factor of psycho-
logical disorders. Recently, the effect of polyunsatu-
rated fatty acids (PUFAs) on depression has gained
much interest [104,105]. Muller et al. reported a piv-
otal role for membrane-forming omega-3 polyunsatu-
rated fatty acids, glycerophospholipids, sphingolipids,
and glycerolipids in the induction of depression- and
anxiety-related behaviors. In their opinion, these PUFA
also provide new treatment options (e.g. targeted die-
tary supplementation or pharmacological interference
with lipid-regulating enzymes) [106].
A meta-analysis of double-blind, placebo-controlled
studies found a significant antidepressant effect of ma-
rine n-3 PUFAs in patients with clearly defined depres-
sion [107]. Another meta-analysis of 12 studies, most
of which were conducted in clinical settings, compar-
ing blood PUFAs status of patients suffering from de-
pression and controls have also established lower levels
of EPA, DHA, and n-3 PUFAs in patients with depres-
sion [108]. Additionally, erythrocyte or serum choles-
teryl esters levels of ALA were significantly lower in
depressive patients than among healthy controls
As previously mentioned, the distribution of unsatu-
rated fatty acids at the level of the brain tissue is age-
related, with a prevalence of DHA during aging and a
consequent reduction of AA levels in the neuronal
membranes. During conditions of psychological stress,
the production of pro-inflammatory cytokines is in-
creased. Therefore, the unbalance between the two
PUFA pathways generates an excess of pro-
inflammatory cytokines and eicosanoids, which are
participating in the mechanisms of depression patho-
physiology. The literature highlights how the increment
of the omega-6/omega-3 ratio corresponds to an in-
crease in depressive symptoms and the formation of
pro-inflammatory cytokines (e.g. TNF and IL-6) and
related receptors [111]. Hence, a high omega-6/omega-
3 ratio enhances both depression and inflammatory dis-
eases. For example, in post-mortem studies carried out
on brain tissue of depressed patients, a deficit of DHA
was found, and this was partially related to a lower ef-
ficiency of the delta-5 desaturase [112]. Therefore, a
high AA/DHA ratio can be considered an optimal bio-
marker for depression. It is worth underlining that de-
pression is a multifactorial disease, which also depends
on genetic predisposition, environmental factors, and
lifestyle. Also, the intrinsic characteristics of the blood-
brain barrier (BBB) should be considered because,
when altered, this affects the transfer of essential fatty
acids in the central nervous system.
Since the fatty acid composition of a diet and serum
has been linked to depression, the association between
fatty acid composition in serum and depressive symp-
toms in men and woman of Japan has been examined.
A cross-sectional study on 496 participants aged 21–67
826 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.
years indicated that fatty acid composition with high
levels of serum ALA and linoleic acids might be pro-
tectively related with depressive symptoms in Japanese
adults. A higher free ALA level was marginally sig-
nificantly correlated with a diminished prevalence of
depressive syndromes. The research in question also
showed that the other polyunsaturated fatty acids, in-
cluding marine-derived n-3 PUFA, were not linked
with depressive symptoms [113].
Moreover, a low omega-3 PUFA status, and in-
creased risk of depression was observed in patients
who have suffered from a myocardial infarction. Ran-
domized, double-blind, placebo-controlled experiments
were included to evaluate whether ALA and EPA and
DHA from fish would improve affective states. No dif-
ference was observed in regard of depressive syn-
dromes or dispositional optimism amongst study
groups. Thus, in the research neither low-dose EPA-
DHA administration, ALA supplementation, nor an
arrangement of both affected depressive syndromes or
disposable optimism [114].
Alzheimer’s disease (AD) has been listed as the
most common type of dementia that affects ca. 36 mil-
lion people in the world. In majority of people, syn-
drome of memory loss and cognitive impairment ini-
tially present in elderly stage of life (above 65 years
old). Mentioned signs and symptoms become more and
more severe along with AD progression and very often
eventually lead to dead. AD is perceived as a disorder
with huge cost. Growing elderly population and the
lack of treatment that would prevent, slow down or
stop the illness progress, future AD prevalence is pre-
dicted to escalate to an extent that it may threaten the
maintenance and stability of healthcare systems
worldwide. Therefore, there is a need for a global effort
for a more complete understanding of this disease, with
the aim of designing a method of treatment that could
prevent, limit or block AD progressions [115].
The importance of the optimal balance between the
omega-6 and omega-3 pathways is also confirmed by
research conducted on Alzheimer's disease that has
shown a marked reduction of DHA levels in the hippo-
campus, connected with a reduction of plasmalogens,
which are an important class of neuronal phospholip-
ids. Both DHA and plasmalogens are abundantly pre-
sent in synaptosomes, which constitute the vesicles
containing the neurotransmitters. Therefore, this dec-
rement can be associated with the loss of synapses and
damage to cognitive function, which are typical events
in AD [51,116]. Preliminary clinical studies presented
by Yehuda et al. showed that administration of a com-
position of LA and ALA, at a ratio of 4:1, improves
score in quality of life test for Alzheimer’s patients, as
measured by the mini-mental state examination
(MMSE/ Folstein test), a questionnaire evaluating cog-
nitive impairment [117]. Research introduced by Ha-
shimoto et al. revealed that treatments with different
proportion have not advanced the condition of Alz-
heimer’s patients and also administration of a single
fatty acid, i.e. omega-3 DHA, has not improved the
condition of Alzheimer’s patients considerably. Simul-
taneously, it has been confirmed that pre-
administration of DHA had a significantly advanta-
geous influence on the decrease in learning skills in
Alzheimer's disease rat model [118]. In addition, re-
search conducted on epidemiological basis has also
revealed a promising protective character of omega-3
polyunsaturated fatty acids against Alzheimer's disor-
der and, thus, indicate that n-3 PUFAs may be good
candidates for neuronal protective and restorative
strategies against various central nervous system disor-
ders [119,120].
Although, preliminary data confirm that n-3 PUFAs
might act to protect organism against some of the in-
fections and cope with inflammatory states as well as
support treatment of numerous clinical conditions (e.g.
ADHD, ulcers, preterm labour, migraine headaches,
psoriasis, emphysema), following controlled clinical
study is still required to complete knowledge about the
specific underlying mechanisms responsible for the
beneficial effects of essential fatty acid: ALA and its
derivatives. [92,121].
Dietary fat is involved in proper development of our
physiology and well-being. It is listed on the second
place of importance when it comes to our inner energy
production, because fat not only delivers fatty acids,
but also helps the body absorb vitamins fundamental
for growth, development, and the maintenance of good
health. However, disproportionate and unnecessary
quantities of omega-6 PUFA responsible for an im-
mensely high omega-6/omega-3 ratio, is observed in
present’s Western diets. Both our sedentary lifestyle
and diet develop the pathogenesis of numerous clinical
conditions (e.g. cancer, cardiovascular disorders, in-
flammatory and autoimmune diseases). The food in-
dustry has already initiated an approach to restore n-3
essential fatty acids into the food sources.
Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 827
Fatty acids from the omega-3 family have been
proven to successfully combat inflammation and
autoimmune disorders, as well as support prevention of
various chronic disorders such as heart disease and ar-
thritis. Given the profound influence, described in this
review, that fatty acids have on membrane properties,
omega-3 PUFAs are essential for homeostasis and the
proper functioning of the central nervous system. It is
clear from the literature that the omega-3 fatty acid
group is involved in a variety of significant processes
in neural cells. Therefore, it is crucial to sustain a re-
quired equilibrium of omega-3 and omega-6 in our
diet. Finally, the balance depends on the dietary contri-
bution and that appears to be a key approach to disease
prevention at the level of the central nervous system.
Thus, dietary supply of precursor ALA or its deriva-
tives EPA and DHA is particularly significant for the
development of the brain tissue and for evolvement of
eyeball membrane (retina), and its preventive role in
brain damaged disorders was revealed as well. The re-
lationship between EFA level, inflammatory states and
central nervous system disorders are an immensely
promising subject and remains to be entirely investi-
AA = arachidonic acid
AD = Alzheimer's disease
ADHD = attention deficit hyperactivity disorder
ALA = alpha-/α-linolenic acid
COX-2 = prostaglandin-endoperoxide synthase 2
DHA = docosahexaenoic acid
EFA = essential fatty acid
EPA = eicosapentaenoic acid
GLA = gamma-/γ-linolenic acid
LA = linoleic acid
MUFA = mono-unsaturated fatty acid
PUFA = polyunsaturated fatty acid
The author(s) confirm that this article content has no
conflict of interest.
Declared none.
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Received: April 04, 20 15 Revised: January 08 , 2016 Accepted: January 22, 2 016
... Omega-3 PUFAs, mainly DHA and eicosapentaenoic acid (EPA) which have strong anti-inflammatory and inflammationresolving effects, also antagonizing the pro-inflammatory effects of omega-6 PUFAs which are the precursors of proinflammatory mediators. The balance between omega-6 PUFAs and omega-3 PUFAs is essential for homeostasis and the proper functioning of the central nervous system (CNS) to promote mental health and prevent neurological diseases (7,8). Since omega-3 PUFAs and omega-6 PUFAs compete for incorporation into cell membranes, a balanced intake of these different type of PUFAs is essential (8). ...
... The balance between omega-6 PUFAs and omega-3 PUFAs is essential for homeostasis and the proper functioning of the central nervous system (CNS) to promote mental health and prevent neurological diseases (7,8). Since omega-3 PUFAs and omega-6 PUFAs compete for incorporation into cell membranes, a balanced intake of these different type of PUFAs is essential (8). In modern society, human diets are unbalanced between omega-3 PUFAs and omega-6 PUFAs that may restrict the supply of omega-3 PUFAs to the tissues leading to a mild or severe omega-3 PUFAs deficiency in both developed and developing countries worldwide (9-12). ...
... There is a considerable amount of literature regarding the mechanism of action of omega-3 PUFAs to improve physical health and brain functioning [see, e.g., (8,14,(16)(17)(18)], and many of them have been further considered as possible mechanisms for omega-3 PUFAs to improve depressive symptoms. Omega-3 PUFAs supplementation in depressed subjects has many structural and functional benefits for the brain, including promoting neurogenesis and neural repairment, preventing neuroinflammation and neurodegeneration, improving mood, cognition and memory etc., thus, exerting a wide range of ameliorating effects on depression (19)(20)(21). ...
Full-text available
Omega-3 polyunsaturated fatty acids (PUFAs) can play important roles in maintaining mental health and resistance to stress, and omega-3 PUFAs supplementation can display beneficial effects on both the prevention and treatment of depressive disorders. Although the underlying mechanisms are still unclear, accumulated evidence indicates that omega-3 PUFAs can exhibit pleiotropic effects on the neural structure and function. Thus, they play fundamental roles in brain activities involved in the mood regulation. Since depressive symptoms have been assumed to be of central origin, this review aims to summarize the recently published studies to identify the potential neurobiological mechanisms underlying the anti-depressant effects of omega-3 PUFAs. These include that of (1) anti-neuroinflammatory; (2) hypothalamus-pituitary-adrenal (HPA) axis; (3) anti-oxidative stress; (4) anti-neurodegeneration; (5) neuroplasticity and synaptic plasticity; and (6) modulation of neurotransmitter systems. Despite many lines of evidence have hinted that these mechanisms may co-exist and work in concert to produce anti-depressive effects, the potentially multiple sites of action of omega-3 PUFAs need to be fully established. We also discussed the limitations of current studies and suggest future directions for preclinical and translational research in this field.
... PUFAs have wide-ranging functions in cardiovascular, pulmonary, and immune systems. [23][24][25][26][27] Recently, n-3 PUFAs have been reported to have various advantageous effects on eye disorders, [28][29][30] and investigation of their suppressive effect on myopia progression has attracted our attention. ...
... N- 3 PUFAs have also been demonstrated to exert anti-allergic and anti-inflammatory effects after conversion to active metabolites, as well as to exert direct effects on the myocardium, vessels, brain, and eyes. 22,24,26,[39][40][41][42][43] Although the ideal ratio in meals of n-6 and n-3 PUFAs has been shown to be 2:1, the consumption of n-6 has increased rapidly, with a ratio of 25:1 since around 1900. 21 This statistic prompted the idea of performing a study to n-3 PUFAs took effects on myopia suppression, enucleated eyes were used for targeted lipidomic analysis, and eicosapentaenoic acid (EPA) were characteristically distributed. ...
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Myopia is increasing worldwide and its preventable measure should urgently be pursued. N‐3 polyunsaturated fatty acids (PUFAs) have been reported to have various effects such as vasodilative and anti‐inflammatory, which myopia may be involved in. This study is to investigate the inhibitory effect of PUFAs on myopia progression. A lens‐induced myopia (LIM) model was prepared using C57B L6/J 3‐week‐old mice, which were equipped with a −30 diopter lens to the right eye. Chows containing two different ratios of n‐3/n‐6 PUFA were administered to the mice, and myopic shifts were confirmed in choroidal thickness, refraction, and axial length in the n‐3 PUFA‐enriched chow group after 5 weeks. To exclude the possibility that the other ingredients in the chow may have taken the suppressive effect, fat‐1 transgenic mice, which can produce n‐3 PUFAs endogenously, demonstrated significant suppression of myopia. To identify what elements in n‐3 PUFAs took effects on myopia suppression, enucleated eyes were used for targeted lipidomic analysis, and eicosapentaenoic acid (EPA) were characteristically distributed. Administration of EPA to the LIM model confirmed the inhibitory effect on choroidal thinning and myopia progression. Subsequently, to identify the elements and the metabolites of fatty acids effective on myopia suppression, targeted lipidomic analysis was performed and it demonstrated that metabolites of EPA were involved in myopia suppression, whereas prostaglandin E2 and 14,15‐dihydrotestosterone were associated with progression of myopia. In conclusion, EPA and its metabolites are related to myopia suppression and inhibition of choroidal thinning.
... Although low-fat diets are recommended, studies have indicated that changing the types of fat consumed can modify the risk of dyslipidemia [49,50]. Since saturated fat intake is currently relatively high among people, replacing these fatty acids with MUFA and PUFA has been associated with a decrease in the incidence of NCDs, especially cardiovascular diseases [51]. This occurs due to decreasing content of TC and LDL-C, which are associated with atherosclerosis [51], as seen in the results of four studies in this systematic review [29,[33][34][35]. ...
... Since saturated fat intake is currently relatively high among people, replacing these fatty acids with MUFA and PUFA has been associated with a decrease in the incidence of NCDs, especially cardiovascular diseases [51]. This occurs due to decreasing content of TC and LDL-C, which are associated with atherosclerosis [51], as seen in the results of four studies in this systematic review [29,[33][34][35]. ...
The effect of avocado (Persea Americana) on weight loss in people with excess body weight remains unclear. Therefore, we aimed to test our hypothesis that the intake of avocados' pulp may be a good strategy to improve anthropometric parameters and consequently metabolic health. For this systematic review and meta-analysis, we searched MEDLINE/Pubmed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) for studies published between database inception and July 2021. Randomized clinical trials (RCT) assessing avocado intake on anthropometric parameters (primary outcome) and metabolic parameters (secondary outcomes) were included. Evidence from RCT were synthesized as differences between standardized mean differences (SMDs) for change in body weight and body composition, comparing the experimental avocado group with control via random-effects meta-analyses. The risk of bias followed the Joanna Briggs Institute. PROSPERO register number of this study is CRD42021266488. From 781 records identified, eight studies with 657 individuals were included. No significant changes in body weight, body mass index, % body fat, and neither in visceral adipose tissue in response to intervention was seen in the avocado group compared to the control group. Also, the pooled results showed no reduction in body weight and composition (SMD= 0.09, 95% CI – 0.06 to 0.25, p=0.25, I²=0%) of avocado in comparison to control. Secondary outcomes showed some potential benefits in metabolic parameters mainly related to lipid profile. Regardless, consumption of avocado did not promote weight gain, further studies are needed to elucidate this effect.
... PUFAs are divided into two major groups i.e., Omega-3 and omega-6, which play a principal role in the formation of the structure and function of nervous and visual systems of humans and have a protective impact against inflammatory and cardiovascular diseases (Wysoczański et al. 2016). Interestingly, most of our microalgae contained a high percentage of omega-3 fatty acids, which exceeds that of many oil sources (Table 4). ...
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Detection of oleaginous microalgae with high lipid productivity is a crucial feature for biofuel and nutraceutical production. Therefore, screening of microalgae from different habitats has become highly significant to face the request on these bioresources. Accordingly, the present study aimed to screen the efficiency of biodiesel feedstock and the ability to accumulate essential fatty acids of four green microalgae (Chlorolobion braunii, Tetradesmus obliquus, Monoraphidium minutum, and Asterarcys quadricellulare), isolated from soil samples of Benha, Egypt. Although T.obliquus was the highest biomass productive species (114.86 mgL-1 d-1), but M. minutum was recorded as the highest species of lipid productivity (29 mg L-1 d-1). Fatty acid profiles of the four microalgae confirmed their suitability for biodiesel production as mentioned by the biodiesel properties within the limits of international standards. Species selection through PROMETHEE and GAIA analysis revealed that C. braunii is the best promising as a potential source for biodiesel production because it has a high saturated fatty acids proportion (39.75%) and shows cetane number (54.99) and low iodine value (100.57) and many other biodiesel properties within the standards limit. In addition, the screened microalgae showed a high percentage of omega fractions in their total fatty acids, whereas Asterarcys quadricellulare and M. minutum have high omega-3 fatty acids content of 34.4% and 28.9%, respectively.
... Hexadecanoic acid (C16:0) and oleic acid (C18:1) are the common FAs observed among different microalgae, which are considered as preferred components for making biodiesel [5]. PUFAs especially omega-3 (ω-3) FA, have long been used as value-added nutraceuticals for the nervous PUFAs especially omega-3 (ω-3) FA, have long been used as value-added nutraceuticals for the nervous system in humans [6,7]. FAs are involved in the metabolic pathway of formation and conversion of most lipid classes, and their composition largely determines their properties and practical use. ...
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Microalgae are considered a promising source for biodiesel. The addition of plant hormone can exert a significant impact on the production of microalgae biomass and lipid accumulation. Nevertheless, the response of microalgae cells to hormones is species- or strain-dependent. It remains controversial which genes involved in strong increase of fatty acids production in response to abscisic acid (ABA) in Chlorella sp. FACHB-8 strain. We investigated cell growth, lipid accumulation, and fatty acid composition when ABA and indol-3-acetic acid (IAA) were used in the growth medium of Chlorella sp. FACHB-8. The four treatments, including 5 mg/L IAA (E1), 10 mg/L IAA (E2), 10 mg/L ABA (E3), the combination of 5 mg/L IAA and 5 mg/L ABA (E4), were found to increase cell growth, but only 10 mg/L ABA treatment could enhance the lipid accumulation. The fatty acid profile was changed by the addition of ABA, making fatty acids afflux from polyunsaturated fatty acids to monounsaturated and saturated fatty acids, which were suitable for diesel application. Furthermore, a transcriptome analysis was conducted, unraveling the differentially expressed genes enriched in fatty acid biosynthesis, fatty acid metabolism, and biosynthesis of the unsaturated fatty acid pathway in response to ABA. Our results clarified the correlation of fatty acid synthesis-related genes and fatty acid profiles, helping understand the potential response mechanism of Chlorella sp. FACHB-8 strain respond to ABA treatment.
... Feed formulated with small portions of microalgae biomass effect positively to organism's physiological growth through developing their immune response ability besides increasing reproductive performance, feed conversion and weight gain (Dinesbabu et al., 2019). In addition, microalgae contain nutritionally valuable fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Adarme-Vega et al., 2012) which can help in development of better immunity (Wysoczański et al., 2016). Therefore, microalgae might be a potential source as animal feedstuff. ...
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In this study, purely isolated marine microalgae from southern coast of Bangladesh were cultured for animal feedstuff. A total of four species were isolated from different coastal aqua-farms. Among the four identified species three species were green microalgae (Chlorella sp., Nannochloropsis sp., and Tetraselmis sp.) and one was brown microalgae (Chaetoceros sp.). Growth curves, productivity and proximate composition of identified microalgae were determined to observe the growth rates and nutritional profile. It was found that Nannochloropsis sp. is the most potential species because of its availability, less culture complexity, higher survivability, much biomass productivity (0.45 mg/L/Day), protein (35%), and carbohydrate (22%) profile. Moreover, Chlorella sp. and Tetraselmis sp. are also found suitable considering its protein (33% and 40%) and carbohydrate (23% and 17%) profile. These all species are found potential as animal feedstuffs considering mainly their protein profile.
... There was a study which also suggested that the supplementation of n-3 PUFAs could improve the memory ability of male Long-Evans rats by inhibiting the neuroinflammation which was induced by interleukin-1β (IL-1β) [64], and that the supplementation of ALA could increase cognitive function [65]. In addition, compared with patients with mild neurocognitive impairment, the EPA and DHA (transformed from ALA [66]) levels in the plasma of patients with severe neurocognitive impairment were lower [67]. Another study also revealed that ALA and DHA protected microglia against a decrease in cell viability in obese people with cognitive impairment [68]. ...
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Dietary fatty acid intake is closely related to the cognitive function of the overweight and obese population. However, few studies have specified the correlation between exact fatty acids and cognitive functions in different body mass index (BMI) groups. We aimed to explain these relationships and reference guiding principles for the fatty acid intake of the overweight and obese population. Normal weight, overweight, and obese participants were recruited to receive a cognitive function assessment and dietary survey, dietary fatty acids intake was calculated, and the erythrocyte membrane fatty acid profile was tested by performing a gas chromatography analysis. The percentages of saturated fatty acids (SFAs) in the obese group were higher, while monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were lower than in the normal weight and overweight groups. In the erythrocyte membrane, the increase of n-3 PUFAs was accompanied by cognitive decline in the overweight group, which could be a protective factor for cognitive function in the obese group. High n-6 PUFAs intake could exacerbate the cognitive decline in the obese population. Dietary fatty acid intake had different effects on the cognitive function of overweight and obese people, especially the protective effect of n-3 PUFAs; more precise dietary advice is needed to prevent cognitive impairment.
... Moreover, elevated plasma TG is associated with CVD risk and therefore TG reduction (which can be achieved through higher omega-3 intake in certain patients) has several potential health benefits (27,34). Omega-3 intake has also demonstrated additional health benefits such as improving major depressive disorder in conjunction with other therapies (35)(36)(37), potentially improving cognitive function in very mild Alzheimer's disease (37,38), and improving outcomes of inflammatory diseases (39,40). To mitigate any potential risks, while consuming enough omega-3s to result in possible health benefits, the United States Food and Drug Administration (FDA) states that EPA+DHA supplementation should not exceed 5.0 g/day (41). ...
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Background A recent systematic review, which used the GRADE methodology, concluded that there is strong evidence for two gene-diet associations related to omega-3 and plasma triglyceride (TG) responses. Systematic reviews can be used to inform the development of clinical practice guidelines (CPGs). Objective To provide guidance for clinical practice related to genetic testing for evaluating responsiveness to dietary/supplemental omega-3s and their impact on plasma lipids/lipoproteins/apolipoproteins. Design Using the results of the abovementioned systematic review, the first CPGs in nutrigenetics were developed using the established GRADE methodology and AGREE II approach. Results Three clinical practice recommendations were developed. Most gene-diet associations identified in the literature lack adequate scientific and clinical validity to warrant consideration for implementing in a practice setting. However, two gene-diet associations with strong evidence (GRADE quality: moderate and high) can be considered for implementation into clinical practice in certain cases: male APOE -E4 carriers (rs429358, rs7412) and TG changes in response to the omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) as well as a 31-SNP nutrigenetic risk score and TG changes in response to EPA+DHA among adults with overweight/obesity. Ethical and regulatory implications must be considered when providing APOE nutrigenetic tests given the well-established link between APOE genetic variation and Alzheimer's Disease. Conclusion Most of the evidence in this area is not ready for implementation into clinical practice primarily due to low scientific validity (low quality of evidence). However, the first CPGs in nutrigenetics have been developed for two nutrigenetic associations with strong scientific validity, related to dietary/supplemental omega-3 and TG responses.
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Flavonoids belong to the polyphenol superfamily and present in our foods derived from natural sources including fruits and vegetables. Apigenin and Chrysin, prominent flavonoids have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to alter cellular metabolome based on untargeted metabolomics. Based on our metabolomics data, both these structurally related flavonoids demonstrate diverging and converging properties. Apigenin demonstrated the potential to possess anti-inflammatory and vasorelaxant properties through the upregulation of alpha-linolenic acid and linoleic acid metabolism intermediates. Chrysin on the other hand exhibited abilities to inhibit protein and pyrimidine synthesis along with downregulation of gluconeogenesis pathways based on the metabolites obtained. These metabolic effects were due to the impact of chrysin to modulate L-alanine metabolism and urea cycle. On the other hand, both the flavonoids demonstrated converging effects by their ability to downregulate metabolites involved in cholesterol biosynthesis and uric acid synthesis namely 7-dehydrocholesterol and xanthosine respectively. Our work could provide understanding regarding the various therapeutic potential of these naturally occurring flavonoids which are food constituents to treat metabolic complications in conditions like obesity, diabetes, cancer, and cardiovascular diseases. Further investigation of these natural agents for targeted diseases using whole animal and translational approaches will validate their therapeutic ability and help in curbing an array of metabolic complications.
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Alterations of the immune system could seriously impair the ability to combat infections during future long-duration space missions. However, little is known about the effects of spaceflight on the B-cell compartment. Given the limited access to astronaut samples, we addressed this question using blood samples collected from 20 healthy male volunteers subjected to long-duration bed rest, an Earth-based analog of spaceflight. Hematopoietic progenitors, white blood cells, total lymphocytes and B-cells, four B-cell subsets, immunoglobulin isotypes, six cytokines involved in inflammation, cortisone and cortisol were quantified at five time points. Tibia microarchitecture was also studied. Moreover, we investigated the efficiency of antioxidant supplementation with a cocktail including polyphenols, omega 3, vitamin E and selenium. Our results show that circulating hematopoietic progenitors, white blood cells, total lymphocytes and B-cells, and B-cell subsets were not affected by bed rest. Cytokine quantification suggested a lower systemic inflammatory status, supported by an increase in serum cortisone, during bed rest. These data confirm the in vivo hormonal dysregulation of immunity observed in astronauts and show that bed rest does not alter B-cell homeostasis. This lack of an impact of long-term bed rest on B-cell homeostasis can, at least partially, be explained by limited bone remodeling. None of the evaluated parameters were affected by the administration of the antioxidant supplement. The non-effectiveness of the supplement may be because the diet provided to the non-supplemented and supplemented volunteers already contained sufficient antioxidants. Given the limitations of this model, further studies will be required to determine whether B-cell homeostasis is affected, especially during future deep-space exploration missions that will be of unprecedented durations.
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In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the aging brain affect the neuronal membrane that is the "site of action" for many essential functions learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total PUFA may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incomrporation into the membrane. Administration of a ratio of 1: 4 of omega 3/omega 6 PUFA may improve the neuronal membrane functions and behavior of the aging brain.
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Brain endothelial cells are unique among endothelial cells in that they express apical junctional complexes, including tight junctions, which quite resemble epithelial tight junctions both structurally and functionally. They form the blood-brain-barrier (BBB) which strictly controls the exchanges between the blood and the brain compartments by limiting passive diffusion of blood-borne solutes while actively transporting nutrients to the brain. Accumulating experimental and clinical evidence indicate that BBB dysfunctions are associated with a number of serious CNS diseases with important social impacts, such as multiple sclerosis, stroke, brain tumors, epilepsy or Alzheimer's disease. This review will focus on the implication of brain endothelial tight junctions in BBB architecture and physiology, will discuss the consequences of BBB dysfunction in these CNS diseases and will present some therapeutic strategies for drug delivery to the brain across the BBB.
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Omega-3 polyunsaturated fatty acids (n-3 PUFAs), commonly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been acknowledged as essential long-chain fatty acids imposing either optimal health promotion or the rescuing from chronic inflammatory diseases such as atherosclerosis, fatty liver, and various inflammatory gastrointestinal diseases. Recent studies dealing with EPA and DHA have sparked highest interests because detailed molecular mechanisms had been documented with the identification of its receptor, G protein coupled receptor, and GPR120. In this review article, we have described clear evidences showing that n-3 PUFAs could reduce various Helicobacter pylori - ( H. pylori -) associated gastric diseases and extended to play even cancer preventive outcomes including H. pylori -associated gastric cancer by influencing multiple targets, including proliferation, survival, angiogenesis, inflammation, and metastasis. Since our previous studies strongly concluded that nonantimicrobial dietary approach for reducing inflammation, for instance, application of phytoceuticals, probiotics, natural products including Korean red ginseng, and walnut plentiful of n-3 PUFAs, might be prerequisite step for preventing H. pylori -associated gastric cancer as well as facilitating the rejuvenation of precancerous atrophic gastritis, these beneficial lipids can restore or modify inflammation-associated lipid distortion and correction of altered lipid rafts to send right signaling to maintain healthy stomach even after chronic H. pylori infection.
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In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). Parkinson's disease (PD), a degeneration of nigro-striatal DA neurons is the most conspicuous reflection of the vulnerability of DA neurons to age. In this context, cell reprogramming offers novel therapeutic possibilities for the treatment of these devastating diseases. In effect, the generation of induced pluripotent stem cells (iPSCs) from somatic cells demonstrated that adult mammalian cells can be reprogrammed to a pluripotent state by the overexpression of a few embryonic transcription factors (TF). This discovery fundamentally widened the research horizon in the fields of disease modeling and regenerative medicine. Although it is possible to re-differentiate iPSCs to specific somatic cell types, the tumorigenic potential of contaminating iPSCs that failed to differentiate, increases the risk for clinical application of somatic cells generated by this procedure. Therefore, reprogramming approaches that bypass the pluripotent stem cell state are being explored. A method called lineage reprogramming has been recently documented. It consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage-specific TF or microRNAs. Another approach, termed direct reprogramming, features several advantages such as the use of universal TF system and the ability to generate a rejuvenated multipotent progenitor cell population, able to differentiate into specific cell types in response to a specific differentiation factors. These novel approaches offer a new promise for the treatment of pathologies associated with the loss of specific cell types as for instance, nigral DA neurons (in PD) or basal forebrain cholinergic neurons in the early stages of AD. The above topics are reviewed here.
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Major depression and anxiety disorders have high prevalence rates and are frequently comorbid. The neurobiological bases for these disorders are not fully understood, and available treatments are not always effective. Current models assume that dysfunctions in neuronal proteins and peptide activities are the primary causes of these disorders. Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane’s function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors. These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment.
Attention-deficit hyperactivity disorder (ADHD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. ADHD is a widespread condition that is of public health concern. In most children with ADHD the cause is unknown, but is thought to be biological and multifactorial. Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n−3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n−3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors involving fatty acid intake, conversion of EFAs to LCPUFA products, and enhanced metabolism are discussed. The relation between LCPUFA status and the behavior problems that the children exhibited is also unclear. We are currently testing this relation in a double-blind, placebo-controlled intervention in a population of children with clinically diagnosed ADHD who exhibit symptoms of EFA deficiency.
A 6-yr-old girl who lost 300 cm of intestine was maintained by total parenteral nutrition. After 5 months on a preparation rich in linoleic acid but low in linolenic acid she experienced episodes of numbness, paresthesia, weakness, inability to walk, pain in the legs, and blurring of vision. Diagnostic analysis of fatty acids of serum lipids revealed marginal linoleate deficiency and significant deficiency of linolenate. When the regimen was changed to emulsion containing linolenic acid neurological symptoms disappeared. Analysis indicated that linoleate deficiency had worsened but linolenate deficiency had been corrected. The requirement for linolenic acid is estimated to be about 0.54% of calories.
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