ArticlePDF AvailableLiterature Review

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

January 2016
Current Medicinal Chemistry 23(999)

DOI:10.2174/0929867323666160122114439

Authors:

Jolanta Pekala

Wrocław University of Science and Technology

Stanisław Lochyński

Wrocław University of Science and Technology

Show all 9 authorsHide

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.

Content uploaded by Katarzyna Czyż

Content may be subject to copyright.

Send Ord ers for Reprints to reprints@benthamscience.ae

816 Current Medicinal Chemistry, 2016, 23, 816-831

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

Review

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

The

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.

INTRODUCTION

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:

pekala.jolanta@gmail.com and Department of Radioligands, Colle-

gium Medicum, Jagiellonian University, Medyczna 9, 30-688

Kraków, Poland; Tel: +48126205530; Fax: +4812 6205552;

E-mail: mflibrow@cyf-kr.edu.pl

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

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).

IMPORTANCE OF FAT

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-

10].

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.

ESSENTIAL FATTY ACIDS

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; 18:26), 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, 18:33) 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)

[12,13].

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

n6 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

Omega-6

Linolenic Acid C18:3

Omega-3

Arachidonic Acid

C20:4

Omega-6

Docosahexaenoic

Acid C22:6

Omega-3

Omega-6 fatty acid Omega-3 fatty acid

C18:2n-6 C18:3n-3

Formation of new double bond

C18:3

C18:4

LA – Linoleic Acid:

Corn oil

:ALA – -Linoleic Acid:

Flaxseed oil

Canola oil

C18:3

C18:4

Increase in chain length

C20:3n-6 C20:4n-3

Formation of new double bond

afflower oil

Sunflower oil

Canola

oil

Soybean oil

C20:4n-6 C20:5n-3

Increase in chain length

C22:5

C22:6

AA – Arachidonic Acid: :EPA – Eicosapentaenoic Acid

Oily fish

Fish oil capsules

:DHA

–

Docosahexaenoic Acid

C22:5

C22:6

:DHA

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-

branes.

Table 1. Alpha-Linolenic a cid content of various oils

and common foods [23,31,32].

PRODUCT α-Linolenic acid, % by wt

FLAXSEED OIL 50.8

SOY OIL 7.0

CANOLA OIL 9.3

OLIVE OIL 0.6

CHOCOLATE 0.1

CORN OIL 1.0

COCONUT OIL < 0,01

SAFFLOWER OIL 0.4

HAZELNUTS, DRY

ROASTED 0.2

ALMONDS, DRY ROASTED 0.4

SPINACH 0.12

BRUSSELS SPROUTS 0.20

KALE 0.13

OMEGA-3 PUFAS ARE ESSENTIAL FOR HO-

MEOSTASIS AND THE PROPER FUNCTION-

ING OF THE CENTRAL NERVOUS SYSTEM

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].

THE SIGNIFICANCE OF THE OMEGA-

6/OMEGA-3 RATIO

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

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 AND THE INTEG-

RITY OF THE BLOOD-BRAIN BARRIER

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

content.

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].

AGING

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)

[67,68].

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

[69].

Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 823

MEMBRANE FLUIDITY

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].

GENE EXPRESSION

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.

SLEEP DISORDERS

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].

ADHD

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].

DEPRESSION

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

[109,110].

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

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].

SUMMARY

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-

gated.

ABBREVIATIONS

AA = arachidonic acid

AD = Alzheimer's disease

ADHD = attention deficit hyperactivity disorder

ALA = alpha-/α-linolenic acid

COX-2 = prostaglandin-endoperoxide synthase 2

inhibitor

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

CONFLICT OF INTEREST

The author(s) confirm that this article content has no

conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Simopoulos, A.P. Evolutionary aspects of omega-3 fatty

acids in the food supply. Prostaglandins Leukot. Essent.

Fatty Acids, 1999, 60(5-6), 421-429.

[2] Zivkovic, A.M.; Telis, N.; German, J.B.; Hammock, B.D.

Dietary omega-3 fatty acids aid in the modulation of

inflammation and metabolic health. Calif. Agric. (Berkeley),

2011, 65(3), 106-111.

[3] Holman, R.T.; Johnson, S.B.; Hatch, T.F. A case of human

linolenic acid deficiency involving neurological

abnormalities. Am. J. Clin. Nutr., 1982, 35(3), 617-623.

[4] Tsubura, A.; Yuri, T.; Yoshizawa, K.; Uehara, N.; Takada,

H. Role of fatty acids in malignancy and visual impairment:

epidemiological evidence and experimental studies. Histol.

Histopathol., 2009, 24(2), 223-234.

[5] Crupi, R.; Marino, A.; Cuzzocrea, S. n-3 fatty acids: role in

neurogenesis and neuroplasticity. Curr. Med. Chem., 2013,

20(24), 2953-2963.

[6] Yehuda, S. Omega-6/omega-3 ratio and brain-related

functions. World Rev. Nutr. Diet, 2003, 92, 37-56.

[7] Aranceta, J.; Perez-Rodrigo, C. Recommended dietary

reference intakes, nutritional goals and dietary guidelines

for fat and fatty acids: a sy stematic review. Br. J. Nutr.,

2012, 107(Suppl) 2S8-22.

[8] Flock, M.R.; Harris, W.S.; Kris-Etherton, P.M. Long-chain

omega-3 fatty acids: time to establish a dietary reference

intake. Nutr. Rev., 2013, 71(10), 692-707.

[9] Trumbo, P.; Schlicker, S.; Yates, A.A.; Poos, M. Dietary

reference intakes for energy, carbohydrate, fiber, fat, fatty

acids, cholesterol, protein and amino acids. J. Am. Diet

Assoc., 2002, 102(11), 1621-1630.

[10] Bjorntorp, P. Importance of fat as a support nutrient for

energy: metabolism of athletes. J. Sports Sci., 1991, 9 Spec

No71-76.

[11] Connor, W.E. α-Linolenic acid in health and disease. Am. J.

Clin. Nutr., 1999, 69(5), 827-828.

[12] Siscovick, D.S.; Raghunathan, T.E.; King, I.; Weinmann,

S.; Wicklund, K.G.; Albright, J.; Bovbjerg, V.; Arbogast,

P.; Smith, H.; Kushi, L.H.; et al. Dietary intake and cell

membrane levels of long-chain n-3 polyunsaturated fatty

acids and the risk of primary cardiac arrest. JAMA, 1995,

274(17), 1363-1367.

[13] Park, J.-M.; Jeong, M.; Kim, E.-H.; Han, Y.-M.; Kwon,

S.H.; Hahm, K.-B. Omega-3 Polyunsaturated Fatty Acids

Intake to Regulate Helicobacter pylori-Associated Gastric

Diseases as Nonantimicrobial Dietary Approach. BioMed.

Res. Int., 2014, Article ID 7123631-11.

[14] Simopoulos, A.P. The importance of the ratio of omega-

6/omega-3 essential fatty acids. Biomed. Pharmacoth er.,

2002, 56(8), 365-379.

[15] Omega-6/Omega-3 Essential Fatty Acid Ratio: The

Scientific Evidence. World Rev Nutr Diet, ed. Simopoulos

AP and Cleland, L. Vol. vol 92. 2003, Basel: Karger.

[16] Connor, W.E.; Neuringer, M.; Reisbick, S. Essential fatty

acids: th e importan ce of n-3 fatty acids in the retina and

brain. Nutr. Rev., 1992, 50(4 ( Pt 2)), 21-29.

[17] Melnik, B.C.; Plewig, G. Is the origin of atopy linked to

deficient conversion of omega-6-fatty acids to prostaglandin

E1? J. Am. Acad. Dermatol., 1989, 21(3 Pt 1), 557-563.

[18] Karlstad, M.D.; D eMichele, S.J.; Leathem, W.D.; Peterson,

M.B. Effect of intravenous lipid emulsions enriched with

gamma-linolenic acid on plasma n-6 fatty acids and

prostaglandin biosynthesis after burn and endotoxin injury

in rats. Crit. Care Med., 1993, 21(11), 1740-1749.

[19] Neuringer, M.; Connor, W.E.; Lin, D.S.; Barstad, L.; Luck,

S. Biochemical and functional effects of prenatal and

postnatal omega 3 fatty acid deficiency on retina and brain

828 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.

in rhesus monkeys. Proc. Natl. Acad. Sci. U S A, 1986,

83(11), 4021-4025.

[20] Fedorova, I.; Hussein, N.; Baumann, M.H.; Di Martino, C.;

Salem, N., Jr. An n-3 fatty acid deficiency impairs rat

spatial learning in the Barnes maze. Behav. Neurosci., 2009,

123(1), 196-205.

[21] Ozias, M.K.; Carlson, S.E.; Levant, B. Maternal parity and

diet (n-3) polyunsaturated fatty acid concentration influence

accretion of brain phospholipid docosahexaenoic acid in

developing rats. J. Nutr., 2007, 137(1), 125-129.

[22] Ollis, T.E.; Meyer, B.J.; Howe, P.R. Australian food

sources and intakes of omega-6 and omega-3

polyunsaturated fatty acids. Ann. Nutr. Metab., 1999, 43(6),

346-355.

[23] Meyer, B .J.; Mann, N.J.; Lewis, J.L.; Milligan, G.C.;

Sinclair, A.J.; Howe, P.R. Dietary intakes and food sources

of omega-6 and omega-3 polyunsaturated fatty acids.

Lipids, 2003, 38(4), 391-398.

[24] Dobryniewski, J.; Szajda, S.D.; Waszkiewicz, N.; Zwierz,

K. Biology of essential fatty acids (EFA). Przegl. Lek.,

2007, 64(2), 91-99.

[25] Trappe, T.A.; Fluckey, J.D.; White, F.; Lambert, C.P.;

Evans, W.J. Skeletal muscle PGF(2)(alpha) and PGE(2) in

response to eccentric resistance exercise: influence of

ibuprofen acetaminophen. J. Clin. Endocrinol. Metab.,

2001, 86(10), 5067-5070.

[26] Kiecolt-Glaser, J.K.; Glaser, R.; Christian, L.M. Omega-3

fatty acids and stress-induced immune dysregulation:

implications for wound healing. Mil. Med., 2014, 179(11

Suppl), 129-133.

[27] Patterson, E .; Wall, R.; Fitzgerald, G.F.; Ross, R.P.;

Stanton, C. Health implications of high dietary omega-6

polyunsaturated Fatty acids. J Nutr Metab, 2012,

2012539426.

[28] Calder, P.C. Omega-3 polyunsaturated fatty acids and

inflammatory processes: nutrition or pharmacology? Br. J.

Clin. Pharmacol., 2013, 75(3), 645-662.

[29] Kannan, V.; S ., S.; M., V.D., Textbook of Biochemistry for

Medical Students. Vol. 7. 2013, New Delhi: Jaypee

Brothers Medical Publishers. 791.

[30] de Lorgeril, M.; Renaud, S.; Mamelle, N.; Salen, P.; Martin,

J.L.; Monjaud, I.; Guidollet, J.; Touboul, P.; Delaye, J.

Mediterranean alpha-linolenic acid-rich diet in secondary

prevention of coronary heart disease. Lancet, 1994,

343(8911), 1454-1459.

[31] Chapman, D.J.; De-Felice, J.; Barber, J. Growth

temperature effects on thylakoid membrane lipid and

protein content of pea chloroplasts. Plant Physiol., 1983,

72(1), 225-228.

[32] Nettleton, J.A. Omega-3 fatty acids: comparison of plant

and seafood sources in human nutrition. J. Am. Diet. Assoc.,

1991, 91(3), 331-337.

[33] Chang, C.Y.; Ke, D.S.; Chen, J.Y. Essential fatty acids and

human brain. Acta Neurol. Taiwan, 2009, 18(4), 231-241.

[34] Singh, M. Essential fatty acids, DHA and human brain.

Indian J. Pediatr., 2005, 72(3), 239-242.

[35] Uauy, R.; Dangour, A.D. Nutrition in brain development

and aging: role of essential fatty acids. Nutr. Rev., 2006,

64(5 Pt 2), S24-S33; discussion S72-S91.

[36] Wainwright, P.E. Dietary essential fatty acids and brain

function: a developmental perspective on mechanisms.

Proc. Nutr. Soc., 2002, 61(1), 61-69.

[37] Richardson, A. Can we improve our brain health? J. Fam.

Health Ca re, 2014, 24(6), 28-30.

[38] Rapoport, S.I. In vivo fatty acid incorporation into brain

phosholipids in relation to plasma availability, signal

transduction and membrane remodeling. J. Mol. Neu rosci.,

2001, 16(2-3), 243-261; discussion 279-284.

[39] Bourre, J.M.; Francois, M.; Youyou, A.; Dumont, O.;

Piciotti, M.; Pascal, G.; Durand, G. The effects of dietary

alpha-linolenic acid on the composition of nerve

membranes, enzymatic activity, amplitude of

electrophysiological parameters, resistance to poisons and

performance of learning tasks in rats. J. Nutr., 1989,

119(12), 1880-1892.

[40] Sun, G.Y. Effects of a fatty acid deficiency on lipids of

whole brain, microsomes, and myelin in the rat. J. Lipid

Res., 1972, 13(1), 56-62.

[41] Tahin, Q.S.; Blum, M.; Carafoli, E. The fatty acid

composition of subcellular membranes of rat liver, heart,

and brain: diet-induced modifications. Eur. J. Biochem.,

1981, 121(1), 5-13.

[42] Bourre, J.M.; Pascal, G.; Durand, G.; Masson, M.; Dumont,

O.; Piciotti, M. Alterations in the fatty acid composition of

rat brain cells (neurons, astrocytes, and oligodendrocytes)

and of subcellular fractions (myelin and synaptosomes)

induced by a diet devoid of n-3 fatty acids. J. Neurochem.,

1984, 43(2), 342-348.

[43] Carrie, I.; Clement, M.; de Javel, D.; Frances, H.; Bourre,

J.M. Specific phospholipid fatty acid composition of brain

regions in mice. Effects of n-3 polyunsaturated fatty acid

deficiency and phospholipid supplementation. J. Lipid Res.,

2000, 41(3), 465-472.

[44] Pasenkiewicz-Gierula, M.; Rog, T.; Grochowski, J.; Serda,

P.; Czarnecki, R.; Librowski, T.; Lochynski, S. Effects of a

carane derivative local anesthetic on a phospholipid bilayer

studied by molecular dynamics simulation. Biophys. J.,

2003, 85(2), 1248-1258.

[45] Siemieniuk, A.; Szalkowska-Pagowska, H.; Lochynski, S.;

Piatkowsk i, K.; Filipek, B.; Krupin ska, J.; Czarnecki, R.;

Librowski, T.; Bialas, S. Propranolol analogs containing

natural monoterpene structures: synthesis and

pharmacological properties. Pol. J. Pharmacol. Pharm.,

1992, 44(6), 575-593.

[46] Siemieniuk, A.; Szalkowska-Pagowska, H.; Lochynski, S.;

Piatkowsk i, K.; Filipek, B.; Krupin ska, J.; Czarnecki, R.;

Librowski, T.; Szymanska, I. Synthesis and some

pharmacological properties of 1,2-amino ethers with natural

monoterpene structures. Pol. J. Pharmacol. Pharm., 1992,

44(2), 187-200.

[47] Librowski, T.; Czarnecki, R.; Lochynski, S.; Frackowiak,

B.; Pasenkiewicz-Gierula, M.; Grochowski, J.; Serda, P.

Comparative investigations of hydroxyamine carane

derivative and its R,S-diastereoisomers with strong local

anesthetic activity. Pol. J. Pharmacol., 2001, 53(5), 535-

539.

[48] Evers, A.S.; Elliott, W.J.; Lefkowith, J.B.; Needleman, P.

Manipulation of rat brain fatty acid composition alters

volatile anesthetic potency. J. Clin. Invest., 1986, 77(3),

1028-1033.

[49] Haycock, J.C.; Evers, A.S. Altered phosphoinositide fatty

acid composition, mass and metabolism in brain essential

fatty acid deficiency . Biochim. Biophys. Acta, 1988, 960(1),

54-60.

[50] Bourre, J.M. Effects of nutrients (in food) on the structure

and function of the nervous system: update on dietary

requirements for brain. Part 2 : macronutrients. J. Nutr.

Health Aging, 2006, 10(5), 386-399.

[51] Horrocks, L.A.; Farooqui, A.A. Docosahexaenoic acid in

the diet: its importance in maintenance and restoration of

neural membrane function. Prostaglandins Leukot. Essent.

Fatty Acids, 2004, 70(4), 361-372.

[52] de Vries, H.E.; Kuiper, J.; de Boer, A.G.; Van Berkel, T.J.;

Breimer, D.D. The blood-brain barrier in

neuroinflammatory diseases. Pharmacol. Rev., 1997, 49(2),

143-155.

Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 829

[53] Weiss, N.; Miller, F.; Cazaubon, S.; Couraud, P.O. The

blood-brain barrier in brain homeostasis and neurological

diseases. Biochim. Biophys. Acta, 2009, 1788(4), 842-857.

[54] Strosznajder, J.; Chalimoniuk, M.; Strosznajder, R.P.;

Albanese, V.; Alberghina, M. Arachidonate transport

through the blood-retina and blood-brain barrier of the rat

during aging. Neurosci. Lett., 1996, 209(3), 145-148.

[55] Alberghina, M.; Lupo, G.; Anfuso, C.D.; Infarinato, S.

Differential transport of docosahexaenoate and palmitate

through the blood-retina and blood-brain barrier of the rat.

Neurosci. Lett., 1994, 171(1-2), 133-136.

[56] Avellini, L.; Terracina, L.; Gaiti, A. Linoleic acid passage

through the blood-brain barrier and a possible effect of age.

Neurochem. Res., 1994, 19(2), 129-133.

[57] Terracin a, L.; Brunetti, M.; Avellini, L.; De Medio, G.E.;

Trovarelli, G.; Gaiti, A. Linoleic acid metabolism in brain

cortex of aged rats. Ital. J. Biochem., 1992, 41(4), 225-235.

[58] Innis, S.M. Essential fatty acids in infant nutrition: lessons

and limitations from animal studies in relation to studies on

infant fatty acid requirements. Am. J. Clin. Nutr., 2000,

71(1 Suppl), 238S-244S.

[59] Essential Fatty Acids and Infant Nutrition, ed. Ghisolfi, J.

and Putet, G. 1992, Paris: John Libbey Eurotext. 181.

[60] Pallebage-Gam arallage, M.; Lam, V.; Takechi, R.;

Galloway, S.; Clark, K.; Mamo, J. Restoration of dietary-fat

induced blood-brain barrier dysfunction by anti-

inflammatory lipid-modulating agents. Lipids Health Dis,

2012, 11117.

[61] Takechi, R.; Pallebage-G amarallage, M.M.; Lam, V.; Giles,

C.; Mamo, J.C. Nutraceutical agents with anti-inflammatory

properties prevent dietary saturated-fat induced

disturbances in blood-brain barrier function in wild-type

mice. J. Neuroinflammation, 2013, 1073.

[62] Stolp, H.B.; Johansson, P.A.; Habgood, M.D.;

Dziegielewska, K.M.; Saunders, N.R.; Ek, C.J. Effects of

Neonatal Systemic Inflammation on Blood-Brain Barrier

Permeability and Behaviour in Juvenile and Adult Rats.

Cardiovas. Psychiat. Neurol., 2011, 2011469046.

[63] Pallebage-Gamarallage, M.M.; V., L.; Takechi, R.; S., G.;

L., M.J.C. A Diet Enriched in Docosahexanoic A cid

Exacerbates Brain Parenchymal Extravasation of Apo B

Lipoproteins Induced by Chronic Ingestion of Saturated

Fats. Int. J.Vas. Med., 2012, ID 6476891-6476898.

[64] Kalmijn, S.; Launer, L.J.; Ott, A.; Witteman, J.C.; Hofman,

A.; Breteler, M.M. Dietary fat intake and the risk of

incident dementia in the Rotterdam Study. Ann. Neurol.,

1997, 42(5), 776-782.

[65] Laitinen, M.H.; Ngandu, T.; Rovio, S.; Helkala, E.L.;

Uusitalo, U.; Viitanen, M.; Nissinen, A.; Tuomilehto, J.;

Soininen, H.; Kivipelto, M. Fat intake at midlife and risk of

dementia and Alzheimer's disease: a population-based

study. Dement. Geriatr. Cogn. Disord, 2006, 22(1), 99-107.

[66] Crichton, G.E.; Elias, M.F.; Dore, G.A.; Robbins, M.A.

Relation between dairy food intake and cognitive function:

The Maine-Syracuse Longitudinal Study. Int. Dairy J.,

2012, 22(1), 15-23.

[67] Peters, R. Ageing and the brain. Postgr. Med. J., 2006,

82(964), 84-88.

[68] Lopez-Leon, M.; Reggiani, P.C.; Herenu, C.B.; Goya, R.G.

Regenerative Medicine for the Aging Brain. Enliven. J.

Stem Cell Res. Regen. Med., 2014, 1(1), 1-9.

[69] Yehuda, S. The significance of omega-3/ omega-6 ratio to

aging brain functions. Anti-Aging: Healthy Nutrition &

Cosmetic, 2013 31-34.

[70] Bradbury, J. Docosahexaenoic acid (DHA): an ancient

nutrient for the modern human brain. Nutrients, 2011, 3(5 ),

529-554.

[71] Terracin a, L.; Brunetti, M.; Avellini, L.; De Medio, G.E.;

Trovarelli, G.; Gaiti, A. Arachidonic and palmitic acid

utilization in aged rat brain areas. Mo l. Cell Biochem., 1992,

115(1), 35-42.

[72] Kumar, V.B.; Vyas, K.; Buddhiraju, M.; Alshaher, M.;

Flood, J.F.; Morley, J.E. Changes in membrane fatty acids

and delta-9 desaturase in senescence accelerated (SAMP8)

mouse hippocampus with aging. Life Sci., 1999, 65(16),

1657-1662.

[73] Ilincheta de Boschero, M.G.; Roque, M.E.; Salvador, G.A.;

Giusto, N.M. Alternative pathways for phospholipid

synthesis in different brain areas during aging. Exp.

Gerontol., 2000, 35(5), 653-668.

[74] Denis, I.; Potier, B.; Heberd en, C.; Vancassel, S. Omega-3

polyunsaturated fatty acids and brain aging. Curr.

Opin.Clin. Nutr. Metab. Care, 2015, 18(2), 139-146.

[75] Yehuda, S.; Rabinovitz, S.; Mostofsky, D.I. Essential fatty

acids are mediators of brain biochemistry and cognitive

functions. J. Neurosci. Res., 1999, 56(6), 565-570.

[76] Schengrund, C.L.; Ali-Rahmani, F.; Ramer, J.C.

Cholesterol, GM1, and autism. Neurochem. Res., 2012,

37(6), 1201-1207.

[77] Sawazaki, S.; Hamazaki, T.; Yazawa, K.; Kobayashi, M.

The effect of docosahexaenoic acid on plasma

catecholamine concentrations and glucose tolerance during

long-lasting psychological stress: a double-blind placebo-

controlled study. J. Nutr. Sci. Vitaminol .(Tokyo), 1999,

45(5), 655-665.

[78] Yehuda, S.; Rabinovitz, S.; Carasso, R.L.; Mostofsky, D.I.

The role of polyunsaturated fatty acids in restoring the

aging neuronal membrane. Neurobiol. Aging, 2002, 23(5),

843-853.

[79] Angelie, E.; Bonmartin, A.; Boudraa, A.; Gonnaud, P.M.;

Mallet, J.J.; Sappey-Marinier, D. Regional differences and

metabolic changes in normal aging of the human brain:

proton MR spectroscopic imaging study. AJNR Am. J.

Neuroradiol., 2001, 22(1), 119-127.

[80] McGahon, B.M.; Murray, C.A.; Horrobin, D.F.; Lynch.

Age-related changes in oxidative mechanisms and LTP are

reversed by dietary manipulation. Neurobiol. Aging, 1999,

20(6), 643-653.

[81] Kitajka, K.; Sinclair, A.J.; Weisinger, R.S.; Weisinger,

H.S.; Math ai, M.; Jayasooriya, A .P.; Halver, J.E.; Puskas,

L.G. Effects of dietary omega-3 polyunsaturated fatty acids

on brain gene expression. Proc. Natl. Acad. Sci. U S A,

2004, 101(30), 10931-10936.

[82] Puskas, L.G.; Bereczki, E.; Santha, M.; Vigh, L.; Csanadi,

G.; Spener, F.; Ferdinandy, P.; Onochy, A.; Kitajka, K.

Cholesterol and cholesterol plus DHA diet-induced gene

expression and fatty acid changes in mouse eye and brain.

Biochimie, 2004, 86(11), 817-824.

[83] Gamoh, S.; Hashimoto, M.; Sugioka, K.; Shahdat Hossain,

M.; Hata, N.; Misawa, Y.; Masumura, S. Chronic

administration of docosahexaenoic acid improves reference

memory-related learning ability in young rats.

Neuroscience, 1999, 93(1), 237-241.

[84] Carrie, I.; Clement, M.; de Javel, D.; Frances, H.; Bourre,

J.M. Phospholipid supplementation reverses behavioral and

biochemical alterations induced by n-3 polyunsaturated

fatty acid deficiency in mice. J. Lipid Res., 2000, 41(3),

473-480.

[85] Gominak, S.C.; Stumpf, W.E. The world epidemic of sleep

disorders is linked to vitamin D deficiency. Med.

Hypotheses, 2012, 79(2), 132-135.

[86] McCarty, D.E.; Reddy, A.; Keigley, Q.; Kim, P.Y.; Marino,

A.A. Vitamin D, race, and excessive daytime sleepiness. J.

Clin. Sleep Med., 2012, 8(6), 693-697.

830 Current Medicinal Chemistry, 2016, Vol. 23, No. 8 Wysoczański et al.

[87] Wrzosek, M.; Lukaszkiewicz, J.; Wrzosek, M.; Jakubczyk,

A.; Matsumoto, H.; Piatkiewicz, P.; Radziwon-Z aleska, M.;

Wojnar, M.; Nowicka, G. Vitamin D and the central

nervous system. Pharmacol. Rep., 2013, 65(2), 271-278.

[88] Chagas, C.E.; Bo rges, M.C.; Martini, L.A.; Rogero, M.M.

Focus on vitamin D, inflammation and type 2 diabetes.

Nutrients, 2012, 4(1), 52-67.

[89] Hansen, A.L.; Dahl, L.; Olson, G.; Thornton, D.; Graff,

I.E.; Froyland, L.; Thayer, J.F.; Pallesen, S. Fish

consumption, sleep, daily functioning, and heart rate

variability. J. Clin. Sleep Med., 2014, 10(5), 567-575.

[90] Hansen, A.L.; Dahl, L.; Frøyland, L.; Thayer, J.F. Fish

consumption and heart rate variability: Preliminary results.

J.Psychophysiol., 2010, 24(1), 41-47.

[91] Montgomery, P.; Burton, J.R.; Sewell, R.P.; Spreckelsen,

T.F.; Richardson, A.J. Fatty acids and sleep in UK children:

subjective and pilot objective sleep results from the

DOLAB study--a randomized controlled trial. J. Sleep Res.,

2014, 23(4), 364-388.

[92] Burgess, J.R.; Stev ens, L.; Zhang, W.; Peck, L. Long-chain

polyunsaturated fatty acids in children with attention-deficit

hyperactivity disorder. Am. J. Clin. Nutr., 2000, 71(1

Suppl), 327S-330S.

[93] Stevens, L.J.; Zentall, S.S.; Deck, J.L.; Abate, M.L.;

Watkins, B .A.; Lipp, S.R.; Burgess, J.R. Essential fatty acid

metabolism in boys with attention-deficit hyperactivity

disorder. Am. J. Clin. Nutr., 1995, 62(4), 761-768.

[94] Colter, A.L.; Cutler, C.; Meckling, K.A. Fatty acid status

and behavioural symptoms of attention deficit hyperactivity

disorder in adolescents: a case-control study. Nutr. J., 2008,

78.

[95] Richardson, A.J.; Puri, B.K. A randomized double-blind,

placebo-controlled study of the effects of supplementation

with highly unsaturated fatty acids on ADHD-related

symptoms in children with specific learning difficulties.

Prog. Neuropsychopharmacol. Biol. Psychiat., 2002, 26(2),

233-239.

[96] Gillies, D .; Sinn, J.; Lad, S.S.; Leach, M.J.; Ross, M.J.

Polyunsaturated fatty acids (PUFA) for attention deficit

hyperactivity disorder (ADHD) in children and adolescents.

Cochrane Database Syst. Rev., 2012, 7CD007986.

[97] Storebo, O.J.; Skoog, M.; Damm, D.; Thomsen, P.H.;

Simonsen, E.; Gluud, C. Social skills training for Attention

Deficit Hyperactivity Disorder (ADHD) in children aged 5

to 18 years. Cochrane Database Syst. Rev., 2011(12),

CD008223.

[98] Richardson, A.J.; Ross, M.A. F atty acid metabolism in

neurodevelopmental disorder: a new perspective on

associations between attention-deficit/hyperactivity

disorder, dyslexia, dyspraxia and the autistic spectrum.

Prostaglandins Leukot. Essent. Fatty Acids, 2000, 63(1-2),

1-9.

[99] Richardson, A.J.; Puri, B.K. The potential role of fatty acids

in attention-deficit/hyperactivity disorder. Prostaglandins

Leukot. Essent. Fatty Acids, 2000, 63(1-2), 79-87.

[100] Joshi, K.; Lad, S.; Kale, M.; Patwardhan, B.; Mahadik, S.P.;

Patni, B.; Chaudhary, A.; Bhave, S.; Pandit, A.

Supplementation with flax oil and vitamin C improves the

outcome of Attention Deficit Hyperactivity Disorder

(ADHD). Prostaglandins Leukot Essent. Fatty Acids, 2006,

74(1), 17-21.

[101] Dubnov-Raz, G.; Khoury, Z.; Wright, I.; Raz, R.; Berger, I.

The effect of alpha-linolenic acid supplementation on

ADHD symptoms in children: a randomized controlled

double-blind study. Front. Hum. Neurosci., 2014, 8780.

[102] Richardson, A.J. Omega-3 fatty acids in ADHD and related

neurodevelopmental disorders. Int. Rev. Psychiat., 2006,

18(2), 155-172.

[103] Bloch, M.H.; Qawasmi, A. Omega-3 fatty acid

supplementation for the treatment of children with

attention-deficit/hyperactivity disorder symptomatology:

systematic review and meta-analysis. J. Am. Acad. Child

Adolesc. Psychiat., 2011, 50(10), 991-1000.

[104] Murray, C.J.; Vos, T.; Lozano, R.; Naghavi, M.; Flaxman,

A.D.; Michaud, C.; Memish, Z.A. Disability-adjusted life

years (DALYs) for 291 diseases and injuries in 21 regions,

1990-2010: a systematic analysis for the Global Burden of

Disease Study 2010. Lancet, 2012, 380(9859), 2197-2223.

[105] Murakami, K.; Sasaki, S. Dietary intake and depressive

symptoms: a systematic review of observational studies.

Mol. Nutr. Food Res., 2010, 54(4), 471-488.

[106] Muller, C.P.; Reichel, M.; Muhle, C.; Rhein, C.; Gulbins,

E.; Kornhuber, J. Brain membrane lipids in major

depression and anxiety disorders. Biochim. Biophys. Acta,

2014.

[107] Lin, P.Y.; Su, K.P. A meta-analytic review of double-blind,

placebo-controlled trials of antidepressant efficacy of

omega-3 fatty acids. J. Clin. Psychiat., 2007, 68(7), 1056-

1061.

[108] Lin, P.Y.; Huang, S.Y.; Su, K.P. A meta-analytic review of

polyunsaturated fatty acid compositions in patients with

depression. Biol. Psychiat., 2010, 68(2), 140-147.

[109] Peet, M.; Murphy, B.; Shay, J.; Horrobin, D. Depletion of

omega-3 fatty acid levels in red blood cell membranes of

depressive patients. Biol. Psychiat., 1998, 43(5), 315-319.

[110] Maes, M.; Smith, R.; Christophe, A.; Cosyns, P.; Desnyder,

R.; Meltzer, H. Fatty acid composition in major d epression:

decreased omega 3 fractions in cholesteryl esters and

increased C20: 4 omega 6/C20:5 omega 3 ratio in

cholesteryl esters and phospholipids. J. Affect. Disord.,

1996, 38(1), 35-46.

[111] Simopoulos, A.P. Evolutionary aspects of diet: the omega-

6/omega-3 ratio and the brain. Mol. Neurobiol., 2011,

44(2), 203-215.

[112] Conklin, S.M.; Runyan, C.A.; Leonard, S.; Reddy, R.D.;

Muldoon, M.F.; Yao, J.K. Age-related changes of n-3 and

n-6 polyunsaturated fatty acids in the anterior cingulate

cortex of individuals with major depressive disorder.

Prostaglandins Leukot Essent. Fatty Acids, 2010, 82(2-3),

111-119.

[113] Kurotani, K.; Sato, M.; Ejima, Y.; Kashima, K.; Nanri, A.;

Pham, N.M.; Kuwahara, K.; Mizoue, T. Serum alpha-

linolenic and linoleic acids are inversely associated with

depressive symptoms in adults. e-SPEN J., 2014, 9(1), e7-

e12.

[114] Giltay, E.J.; Geleijnse, J.M.; Kromhout, D. Effects of n-3

fatty acids on depressive symptoms and dispositional

optimism after myocardial infarction. Am. J. Clin . Nutr.,

2011, 94(6), 1442-1450.

[115] Erickson, M.A.; Banks, W.A. Blood-brain barrier

dysfunction as a cause and consequence of Alzheimer's

disease. J. Cereb. Blood Flow Metab., 2013, 33(10), 1500-

1513.

[116] Farooqui, A.A.; Ong, W.Y.; Horrocks, L.A. Plasmalogens,

docosahexaenoic acid and neurological disorders. Adv. Exp.

Med. Biol., 2003, 544335-354.

[117] Yehuda, S.; Rabinovtz, S.; Carasso, R.L.; Mostofsky, D.I.

Essential fatty acids preparation (SR-3) improves

Alzheimer's patients quality of life. Int. J. Neurosci., 1996,

87(3-4), 141-149.

[118] Hashimoto, M.; Hossain, S.; Shimada, T.; Sugioka, K.;

Yamasaki, H.; Fujii, Y.; Ishibashi, Y.; Oka, J.; Shido, O.

Docosahexaenoic acid provides protection from impairment

of learning ability in Alzheimer's disease model rats. J.

Neurochem., 2002, 81(5), 1084-1091.

Omega-3 Fatty Acids and their Role in Central Nervous System Current Medicinal Chemistry, 2016, Vol. 23, No. 8 831

[119] Barberger-Gateau, P.; Samieri, C.; Feart, C.; Plourde, M.

Dietary omega 3 polyunsaturated fatty acids and

Alzheimer's disease: interaction with apolipoprotein E

genotype. Curr. Alzheimer Res., 2011, 8(5), 479-491.

[120] Blondeau, N.; Nguemeni, C.; Debruyne, D.N.; Piens, M.;

Wu, X.; Pan, H.; Hu, X.; Gandin, C.; Lipsky, R.H.;

Plumier, J.C.; Marini, A.M.; Heurteaux, C. Subchronic

alpha-linolenic acid treatment enhances brain plasticity and

exerts an antidepressant effect: a versatile potential therapy

for stroke. Neuropsychopharmacology, 2009, 34(12), 2548-

2559.

[121] Aben, A.; Danckaerts, M. [Omega-3 and omega-6 fatty

acids in the treatment of children and adolescents with

ADHD]. Tijdschr. Psychiatr., 2010, 52(2), 89-97.

Received: April 04, 20 15 Revised: January 08 , 2016 Accepted: January 22, 2 016

Del Río Hortega’s insights into oligodendrocytes: recent advances in subtype characterization and functional roles in axonal support and disease

Article

Full-text available

Mar 2025

Pío Del Río Hortega (1882–1945) was a giant of modern neuroscience and perhaps the most impactful member of Cajal’s School. His contributions to clarifying the structure of the nervous system were key to understanding the brain beyond neurons. He uncovered microglia and oligodendrocytes, the latter until then named mesoglia. Most importantly, the characterization of oligodendroglia subtypes he made has stood the omics revolution that added molecular details relevant to comprehend their biological properties. Astounding as it may seem on today’s eyes, he postulated a century ago that oligodendrocytes provide trophic support to axons, an idea that is now beyond doubt and under scrutiny as dysfunction at the axon-myelin unit is key to neurodegeneration. Here, we revised recent key advancements in oligodendrocyte biology that shed light on Hortega’s ideas a century ago.

Neuro-Nutrition and Exercise Synergy: Exploring the Bioengineering of Cognitive Enhancement and Mental Health Optimization

Article

Full-text available

Feb 2025

The interplay between nutrition, physical activity, and mental health has emerged as a frontier in bioengineering research, offering innovative pathways for enhancing cognitive function and psychological resilience. This review explores the neurobiological mechanisms underlying the synergistic effects of tailored nutritional strategies and exercise interventions on brain health and mental well-being. Key topics include the role of micronutrients and macronutrients in modulating neurogenesis and synaptic plasticity, the impact of exercise-induced myokines and neurotrophins on cognitive enhancement, and the integration of wearable bioelectronics for personalized monitoring and optimization. By bridging the disciplines of nutrition, psychology, and sports science with cutting-edge bioengineering, this review highlights translational opportunities for developing targeted interventions that advance mental health outcomes. These insights are particularly relevant for addressing global challenges such as stress, anxiety, and neurodegenerative diseases. The article concludes with a roadmap for future research, emphasizing the potential of bioengineered solutions to revolutionize preventive and therapeutic strategies in mental health care.

Advancements in the investigation of gut microbiota-based strategies for stroke prevention and treatment

Article

Full-text available

Mar 2025

Stroke represents a predominant cause of mortality and disability on a global scale, impacting millions annually and exerting a considerable strain on healthcare systems. The incidence of stroke exhibits regional variability, with ischemic stroke accounting for the majority of occurrences. Post-stroke complications, such as cognitive impairment, motor dysfunction, and recurrent stroke, profoundly affect patients’ quality of life. Recent advancements have elucidated the microbiota-gut-brain axis (MGBA), underscoring the complex interplay between gut health and brain function. Dysbiosis, characterized by an imbalance in gut microbiota, is significantly linked to an elevated risk of stroke and unfavorable outcomes. The MGBA plays a crucial role in modulating immune function, neurotransmitter levels, and metabolic byproducts, which may intensify neuroinflammation and impair cerebral health. This review elucidates the role of MGBA in stroke pathophysiology and explores potential gut-targeted therapeutic strategies to reduce stroke risk and promote recovery, including probiotics, prebiotics, pharmacological interventions, and dietary modifications. However, the current prevention and treatment strategies based on intestinal flora still face many problems, such as the large difference of individual intestinal flora, the stability of efficacy, and the long-term safety need to be considered. Further research needs to be strengthened to promote its better application in clinical practice.

Organ-Specific Responses to Chronic High-Fat Diets in Mice: Insights into Phospholipid Fatty Acid Distribution

Article

Full-text available

Feb 2025

Background/Objectives: This research aimed to investigate phospholipid fatty acid (PLFA) distribution in the brain, kidneys, and white adipose tissue (WAT) and lipid profiles in response to high-fat diets. Methods: Adult female C57BL/6 mice were fed high-fat diets containing 25% linseed, palm, or sunflower oil for 100 days. The fatty acid composition of dietary oils and tissue PL were analyzed using gas–liquid chromatography. Results: Linseed oil increased n-3 polyunsaturated fatty acids (PUFAs) with subsequent conversion into long-chain n-3 PUFAs in the brain and kidney PL, while only alpha-linolenic acid was elevated in WAT. Palm and sunflower oils resulted in unique PLFA distributions in the kidneys and WAT. Palm oil raised linoleic acid without conversion to pro-inflammatory n-6 PUFAs. Sunflower oil increased saturated palmitic acid, as opposed to the rise in monounsaturated oleic acid. Linseed oil also significantly improved lipid profiles, reducing LDL and increasing HDL levels while enhancing cardiovascular indices. Conclusions: This study demonstrates that dietary oils significantly impact organ-specific PLFA profiles, with linseed oil enriching brain and renal n-3 PUFAs, while palm and sunflower oils induce distinct modifications in the kidney and WAT. Moreover, linseed oil offers notable cardioprotective benefits due to the favorable lipid profile changes. These findings highlight the importance of dietary fat selection in achieving balanced lipid metabolism and suggest that diverse oil combinations may be essential for optimizing health outcomes.

Association of Omega 3 and Omega 6 and Child Development: A Systematic Review

Article

Full-text available

Jul 2022

Introduction: Omega-3 and omega-6 long chain polyunsaturated fatty acids (LCPUFA) are the major components of structural central nervous system. This study aimed to summarize the relationship between omega-3 and/ or omega-6 LCPUFA on children development. Method: Three large databases including Science Direct, Pubmed, and Cochrane were used to identify articles reporting the relationship of omega-3 and/or omega-6 and children development published between 2000 and 2021. The study was included if it was performed among under twelve children and provided the data of omega-3 and/ or omega-6 and cognitive development. This systematic review included both observational and experimental study. The publication bias was check using STROBE checklist. Results: The result showed that 4 articles were included consisted of 3 observational studies and 1 experimental study. Two observational studies reported a significant association between omega-3 and/ or omega-6 and children development. However, the experimental study did not confirm these findings. Publications bias was observed in methodology, where the findings showed a weakness in generalizability. Conclusion: This study concludes that omega-3 and omega-6 might play significant role in children development, but further study is needed to be done.

Pilot system for engineering sustainable aquatic food webs: Utilizing cyanobacteria for continuous secretion of ω-polyunsaturated fatty acids

Article

Full-text available

Mar 2025

Allosteric activation of a cell-type specific GPR120 rescues cognition and extends lifespan of Alzheimer’s disease

Preprint

Full-text available

Oct 2024

Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in ageing. Here, we find that black rice enriched alpha-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA) inhibit amyloid pathology, rescue cognition and extends lifespan in mouse preclinical models of Alzheimer’s disease via allosteric activation of GPR120 in brain resident macrophages and activated microglia. We generate the structures of GPR120 bound to ALA and EDA. We demonstrate that ALA and EDA allosterically modulate and synergistically activate GPR120 for macrophagic phagocytosis and clearance of β-amyloid aggregates in Alzheimer’s disease mice. A cell-type specific deletion of GPR120, or Gαi1 completely abrogates the therapeutic effects of ALA and EDA. This deletion can be rescued by a constitutive active Gαi1Q204L. These findings show a cell-type specific function of GPR120 in the brain and provide an enriched allosteric mechanism of GPR120 activation for the treatment of Alzheimer’s disease.

Is there any association between type of dietary fat and quality of life in hemodialysis patients? A cross-sectional study

Article

Full-text available

Sep 2024

Background Hemodialysis (HD) patients have a low quality of life (QOL), and dietary intakes may impact both somatic and psychosocial aspects of QOL. Nevertheless, the relationship between QOL and different dietary fats has not yet been evaluated. Objective The purpose of this study was to assess the association between QOL and the types/quantities of dietary fats intake in HD patients. Methods In this multi-center cross-sectional study, 251 adult patients under dialysis for at least 3 months were included. Participants’ dietary intakes were collected using a validated 168-item semi-quantitative FFQ during the past year. Moreover, to assess QOL, Kidney Disease Quality of Life Short Form (KDQOL-SF 1/3) was used. The linear regression between QOL and different types of dietary fats was conducted. p < 0.05 was statistically significant. Results Overall, 66 women and 185 men participated in our study. Regression analysis adjusted for total calorie intake showed that there was a negative association between QOL and total fat (95% CI: −0.187, −0.043), SFA (95% CI: −0.688, −0.143), MUFA (95% CI: −0.389, −0.065) and PUFA (95% CI: −0.401, −0.056) when types of dietary fats were individually included to the regression analysis. When all types of dietary fats were simultaneously entered into the analysis, the association between QOL and MUFA (95% CI: −0.243, 1.031) and PUFA (95% CI: −1.159, 0.084) were attenuated. The regression coefficient for SFA remained significant (95% CI: −0.968, −0.138). Also, there was a marginally significant association between SFA and the risk of low QOL was observed when all types of dietary fats were simultaneously entered into the analysis (OR = 1.051, 95% CI: 0.998–1.104). Conclusion Our investigation found a negative association between SFA consumption and QOL among different types of dietary fats. Furthermore, SFA mediated the relationship between QOL, MUFA, PUFA, and total fat. So, modification of dietary fat intake could enhance QOL in HD patients.

Fish skin dressing for wound regeneration: A bioactive component review of omega-3 PUFAs, collagen and ECM

Article

Nov 2024
INT J BIOL MACROMOL

Exploring Functional Foods in Prevention of Dementia

Chapter

Aug 2024

Functional foods not only provide energy and nutrients to the body, but they also improve one or more other desirable functions in the body that either help promote health or reduce the risk of disease in the body. Nutrients work in several biochemical and metabolic pathways, and evidences show their neuroprotective effects for protecting against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau, and cell death. There are studies assessing the effects of functional foods on dementia. This study aimed to evaluate the role of functional foods for the prevention of dementia. We review different studies and the mechanisms of functional foods. In the current chapter, we review studies on phenols, microalgae, fungi, grains, fibers, omega-3, vegetables, etc. Some other functional foods are described in other chapters. In sum, functional foods can have the protective roles in the body against dementia due to different properties such as antioxidant and anti-inflammatory properties.

The significance of omega-3/omega-6 ratio to aging brain functions

Article

Full-text available

Mar 2013
AGRO FOOD IND HI TEC

Shlomo -- Yehuda

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.

The blood-brain barrier in brain homeostasis and neurological diseases

Article

Full-text available

Jan 2009
Biochim Biophys Acta

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.

Omega-3 Polyunsaturated Fatty Acids Intake to Regulate Helicobacter pylori-Associated Gastric Diseases as Nonantimicrobial Dietary Approach

Article

Full-text available

Aug 2015
BMRI

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.

Regenerative Medicine for the Aging Brain

Article

Full-text available

Feb 2015

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.

Brain membrane lipids in major depression and anxiety disorders

Article

Full-text available

Dec 2014
BBA-MOL CELL BIOL L

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.

Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder

Article

Jan 2000

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 case of human linolenic acid deficiency involving neurological abnormalities

Article

Mar 1982

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.

Omega-6/omega-3 essential fatty acid ratio: the scientific evidence

Article

Jan 2004
Scand J Nutr

Importance of the Ratio of Omega 6/Omega 3 Essential Fatty Acids - Evolutionary Aspects, Simopoulos, A.P. The Importance of Omega 6/Omega 3 Fatty Acid Ratio in Cell Function - The Gene Transfer of Omega-3 Fatty Acid Desaturase, Kang, J.X. Omega 6/Omega 3 Ratio and Brain-Related Functions, Yehuda, S. Dietary Prevention of Coronary Heart Disease - Focus on Omega 6/Omega 3 Essential Fatty Acid Balance, de Lorgeril, M., Salen, P. Effects of an Indo-Mediterranean Diet on the Omega 6/Omega 3 Ratio in Patients at High Risk of Coronary Artery Disease - The Indian Paradox, Pella, D., Dubnov, G., Singh, R.B., Sharma, R. Berry, E.M. Manor, O. Omega 6/Omega 3 Fatty Acid Ratio - The Israeli Paradox, Dubnov, G., Berry, E.M. Linoleic Acid to Alpha-Linolenic Acid Ratio - From Clinical Trials to Inflammatory Markers of Coronary Artery Disease, Zampelas, A., Paschos, G., Rallidis, L., Yiannakouris, N. The Japan Society for Lipid Nutrition Recommends to Reduce the Intake of Linoleic Acid. A Review and Critique of the Scientific Evidence, Hamazaki, T., Okuyama, H. Omega 6/Omega 3 Polyunsaturated Fatty Acid Ratio and Cancer, Chaj s, V., Bougnoux, P. Omega 6/Omega 3 Fatty Acids and Arthritis, Cleland, L.G., James, M.J., Proudman, S.M.

Evolutionary aspects of W3 fatty acids in the food supply.

Article