1: Int J Clin Pract 2000 Jan-Feb;54(1):57-63
Eicosapentaenoic acid treatment in schizophrenia associated withsymptom remission, normalisation of blood fatty acids, reduced neuronalmembrane phospholipid turnover and structural brain changes.
Puri BK, Richardson AJ, Horrobin DF, Easton T, Saeed N, Oatridge A,Hajnal JV, Bydder GM MRI Unit, Hammersmith Hospital, London, UK.

The administration of the omega-3 fatty acid eicosapentaenoicacid (EPA) to a drug-naive patient with schizophrenia, untreated with conventionalantipsychotic medication, led to a dramatic and sustained clinical improvementin both positive and negative symptoms. This was accompanied by a correctionin erythrocyte membranes of abnormalities in both n-3 and n-6 highly unsaturatedfatty acids and with reduced neuronal membrane phospholipid turnover, asevidenced by serial 31-phosphorus cerebral magnetic resonance spectroscopy.Using recently developed techniques of image segmentation, subvoxel registrationand quantitation, analysis of serial high-resolution 3D cerebral MRI scansshowed that, in the year before EPA treatment, cerebral atrophy was takingplace and that this atrophy was reversed by six months of EPA treatment.These results demonstrate that EPA can reverse both the phospholipid abnormalitiespreviously described in schizophrenia and cerebral atrophy. They providestrong further evidence in support of the membrane phospholipid model ofschizophrenia. PMID: 10750263, UI: 20213847 　 　

The purpose of this article is to describe the professionalliterature and current controversies concerning the relationship betweenessential fatty acids, especially Docohexaenoic Acid (DHA), and neurologicfunction. Although there is debate in the literature concerning just howmuch DHA is required for optimal neurologic functioning of infants, itis known that adequate DHA levels are dependent on an adequate dietaryintake. However, common dietary practices today may not provide enoughDHA. Because pregnancy and lactation are key times of rapid brain growthfor the developing fetus and infant, nurses can be instrumental in teachingpregnant and lactating women diet-related information and promoting practicesthat help increase DHA levels. By understanding the importance of DHA inpregnancy and infancy, the nurse can take a more active role in essentialhealth education. Publication Types: Review Review, tutorial PMID: 10748583,UI: 20212071 　 　

Docosahexaenoic acid (DHA) plays an important role in the nervoussystem. The capacity of the infant to use the essential fatty acid alpha-linolenicacid (ALA) as a substrate for neural DHA has been the subject of much debaterecently. In this study, we explored the metabolic fate of an oral doseof 14C-labeled ALA in guinea pigs fed a defined diet for 3 wk from weaning.Of the 14C-labeled ALA administered, more than 46% was associated withthe skin and fur lipids, mostly in the FFA fraction, and less than 0.1%was in brain lipids. About 39% of the label was not recovered in the bodylipids and was assumed to be expired as CO2 or unabsorbed. The fur andskin were almost equally labeled; however, because of the very low massof ALA in the fur, the specific activity of the fur was very high. Thesedata identify a new route of metabolism of ALA in this species, presumablythrough the sebaceous glands onto fur. If this pathway exists in otherspecies, including humans, it may account for the poor efficiency of conversionof ALA to DHA, because dietary ALA would not be available for anabolicpathways such as DHA synthesis. The relevance of these data to infantsis that ALA may play an important hitherto unidentified role in the skinrelated to barrier function or epidermal integrity. This calls for moreresearch into the importance of ALA as an essential fatty acid in its ownright in human infants. PMID: 10709744, UI: 20172978 　 　

This study investigated the effects of a diet deficient inalpha-linolenic acid followed or not by supplementation with phospholipidsrich in n-3 polyunsaturated fatty acids (PUFA) on behavior and phospholipidfatty acid composition in selected brain regions. Three weeks before mating,two groups of mice were fed a semisynthetic diet containing both linoleicand alpha-linolenic acid or a diet deficient in alpha-linolenic acid. Pupswere fed the same diet as their dams. At the age of 7 weeks, a part ofthe deficient group was supplemented with n-3 PUFA from either egg yolkor pig brain phospholipids for 2 months. In the open field, rearing activitywas significantly reduced in the deficient group. In the elevated plusmaze (anxiety protocol), the time spent on open arms was significantlysmaller in deficient mice than in controls. Using the learning protocolwith the same task, the alpha-linolenic acid deficiency induced a learningdeficit. Rearing activity and learning deficits were completely restoredby supplementation with egg yolk or cerebral phospholipids, though thelevel of anxiety remained significantly higher than that of controls. Therewere no differences among the 4 diet groups for either the Morris watermaze or passive avoidance. In control mice, the level of 22:6 n-3 was significantlyhigher in the frontal cortex compared to all other regions analysed. Thefrontal cortex and the striatum were the most markedly affected by thedeficiency. Supplementation with phospholipids restored normal fatty acidcomposition in brain regions except for frontal cortex. Egg yolk or cerebralphospholipids are an effective source of n-3 PUFA for reversing behavioralchanges and altered fatty acid composition induced by a diet deficientin n-3 PUFA. PMID: 10706595, UI: 20171568 　 　

This study examined the effects of dietary alpha-linolenicacid deficiency followed or not by supplementation with phospholipids richin n;-3 polyunsaturated fatty acid (PUFA) on the fatty acid compositionof total phospholipids in 11 brain regions. Three weeks before mating,mice were fed a semisynthetic diet containing both linoleic and alpha-linolenicacid or deficient in alpha-linolenic acid. Pups were fed the same dietas their dams. At the age of 7 weeks, a part of the deficient group weresupplemented with n;-3 polyunsaturated fatty acids (PUFA) from either eggyolk or pig brain phospholipids for 2 months. Saturated and monounsaturatedfatty acid levels varied among brain regions and were not significantlyaffected by the diet. In control mice, the level of 22:6 n-3 was significantlyhigher in the frontal cortex compared to all regions. alpha-Linolenic aciddeficiency decreased the level of 22:6 n-3 and was compensated by an increasein 22:5 n-6 in all regions. However, the brain regions were affected differently.After the pituitary gland, the frontal cortex, and the striatum were themost markedly affected with 40% reduction of 22:6 n-3. Supplementationwith egg yolk or cerebral phospholipids in deficient mice restored a normalfatty acid composition in brain regions except for the frontal cortex.There was a regional distribution of the fatty acids in the brain and theimpact of deficiency in alpha-linolenic acid was region-specific. Dietaryegg yolk or cerebral phospholipids are an effective source of n-3 PUFAfor the recovery of altered fatty acid composition induced by a diet deficientin n-3 PUFA. PMID: 10706594, UI: 20171567 　 　

Docosahexaenoate (DHA) has been increasingly recognized asan important fatty acid for neural and visual development during the first6 mon of life. One important point of controversy that remains is the degreeto which adequate levels of DHA can be acquired from endogenous synthesisin infants vs. what should be provided as dietary DHA. We have approachedthis problem by a retrospective analysis of published body compositiondata to estimate the actual accumulation of DHA in the human infant brain,liver, adipose tissue, remaining lean tissue, and whole body. Estimatingwhether infants can synthesize sufficient DHA required comparison to andextrapolation from animal data. Over the first 6 mon of life, DHA accumulatesat about 10 mg/d in the whole body of breast-fed infants, with 48% of thatamount appearing in the brain. To achieve that rate of accumulation, breast-fedinfants need to consume a minimum of 20 mg DHA/d. Virtually all breastmilk provides a DHA intake of at least 60 mg/d. Despite a store of about1,050 mg of DHA in body fat at term birth and an intake of about 390 mg/dalpha-linolenate (alpha-LnA), the brain of formula-fed infants not consumingDHA accumulates half the DHA of the brain of breast-fed infants while therest of the body actually loses DHA over the first 6 mon of life. No experimentaldata indicate that formula-fed infants not consuming DHA are able to convertthe necessary 5.2% of alpha-LnA intake to DHA to match the DHA accumulationof breast-fed infants. We conclude that dietary DHA should likely be providedduring at least the first 6 mon of life. Publication Types: Review Review,tutorial PMID: 10695931, UI: 20158478 　 　

In this study, a new marine oil that contains 45% docosahexaenoicacid (DHA, 22:6n-3) and 13% docosapentaenoic acid (DPA, 22:5n-6) was administeredto rats. The metabolism and distribution of DPA in rats was investigated.In experiment 1, the effects of DHA and n-6 fatty acids (linoleic acid,LA; arachidonic acid, AA; and DPA) on AA contents were investigated invivo. LA group: LA 25%, DHA 30%; LA-DPA group: LA 15%, DPA 10%, DHA 35%;LA-AA-DPA group: LA 10%, AA 5%, DPA 10%, DHA 35% were administered to ratsfor 4 wk. In the liver, the AA content in the LA-DPA and LA-AA-DPA groupswas significantly higher than in the LA group. The decreased AA contentsin the LA group might be caused by DHA administration. Although DHA alsowas administered in the LA-DPA and LA-AA-DPA groups, the AA contents inthese two groups did not decrease. These results suggested that DPA retroconvertedto AA, blunting the decrease in AA content caused by DHA administration.To conduct a detailed investigation on DPA metabolism and its relationwith AA and DHA, rat hepatocytes were cultured with purified DPA and DHAfor 24 h. We discovered the retroconversion of DPA to AA occurred onlywhen AA content was decreased by a high DHA administration; it did notoccur when AAcontent was maintained at a normal level. PMID: 10695926,UI: 20158473 　 　

Omega-3 fatty acids (ALA, EPA, DHA) are essential polyunsaturatedfatty acids. Due to their pivotal involvement in signal transduction processesin the CNS, a role for these fatty acids in psychiatric disorders has beenpostulated. This review summarizes the latest findings on the physiologicalfunction of these compounds in the CNS and gives a comprehensive overviewon the emerging therapeutic role of these psychoactive drugs in psychiatricdisorders, with special emphasis being put on affective disorders and schizophrenia.Publication Types: Review Review, tutorial PMID: 10695034, UI: 20159357　 　

Free radical-mediated oxidant injury and lipid peroxidationhave been implicated in a number of neural disorders. We have reportedthat bioactive prostaglandin D2/E2-like compounds, termed D2/E2-isoprostanes,are produced in vivo by the free radical-catalyzed peroxidation of arachidonicacid. Docosahexaenoic acid, in contrast to arachidonic acid, is the mostabundant unsaturated fatty acid in brain. We therefore questioned whetherD/E-isoprostane-like compounds (D4/E4-neuroprostanes) are formed from theoxidation of docosahexaenoic acid. Levels of putative D4/E4-neuroprostanesincreased 380-fold after oxidation of docosahexaenoic acid in vitro from15.2 +/- 6.3 to 5773 +/- 1024 ng/mg of docosahexaenoic acid. Subsequently,chemical approaches and liquid chromatography electrospray ionization tandemmass spectrometry definitively identified these compounds as D4/E4-neuroprostanes.We then explored the formation of D4/E4-neuroprostanes from a biologicalsource, rat brain synaptosomes. Basal levels of D4/E4-neuroprostanes were3.8 +/- 0.6 ng/mg of protein and increased 54-fold after oxidation (n =4). We also detected these compounds in fresh brain tissue from rats atlevels of 12.1 +/- 2.4 ng/g of brain tissue (n = 3) and in human braintissue at levels of 9.2 +/- 4.1 ng/g of brain tissue (n = 4). Thus, thesestudies have identified novel D/E-ring isoprostane-like compounds thatare derived from docosahexaenoic acid and that are formed in brain in vivo.The fact that they are readily detectable suggests that ongoing oxidativestress is present in the central nervous system of humans and animals.Further, identification of these compounds provides a rationale for examiningtheir role in neurological disorders associated with oxidant stress. PMID:10694406, UI: 20160517 　 　

Docosahexaenoic acid (DHA), a 22-carbon long-chain polyunsaturatedfatty acid of the omega-3 family, is a major structural component of neuralmembranes and is a particularly important nutrient during infant development.New safe and well-defined sources of DHA are required for infant formulafortification and dietary supplementation. DHASCO oil is an algal-derivedtriglyceride containing 40-50% DHA. Previous studies have shown that DHASCOoil is neither mutagenic nor toxic in acute or 28-day subchronic tests.To further establish the safety of this oil, a 90-day subchronic toxicitystudy in rats which included haematology, clinical chemistry, pathologyand ophthalmologic, neurobehavioural and neuropathological assessments,using doses of 0.5 and 1.25g/kg body weight/day was performed. There wereno treatment-related adverse effects in any of the parameters measuredat either dose. Based on these results, the no-adverse-effect level (NOAEL)for DHASCO oil under the conditions of this study corresponds to the highestdose level. The DHA in the DHASCO oil was bioavailable, resulting in significantelevations in the levels of this fatty acid in liver, heart and brain after90 days of administration. In conclusion, this 90-day subchronic toxicitystudy provides additional evidence that DHASCO oil is a safe and bioavailablesource of dietary DHA. PMID: 10685012, UI: 20150024 　 　

A critical analysis of the literature of mitochondrial disordersreveals that genetic diseases of oxidative phosphorylation are often associatedwith impaired beta-oxidation, and vice versa, and preferentially affectbrain, retina, heart and skeletal muscle, tissues which depend on docosahexaenoic(22:6n-3)-containing phospholipids for functionality. Evidence suggeststhat an increased NADH/NAD(+) ratio generated by reduced flux through therespiratory chain inhibits beta-oxidation, producing secondary carnitinedeficiency while increasing reactive oxygen species and depleting alpha-tocopherol(alpha-TOC). These events result in impairment of the recently elucidatedmitochondrial pathway for synthesis of 22:6n-3-containing phospholipids,since carnitine and alpha-TOC are involved in their biosynthesis. Therapeuticsupplementation with 22:6n-3 and alpha-TOC is suggested. Publication Types:Review Review, tutorial PMID: 10683429, UI: 20148598 　 　

The aim of the present study was to investigate the maternal-fetaltransport, incorporation, and effects on liver delta-6 fatty-acid desaturaseactivity of dietary trans fatty acids in pregnant rats. Three groups ofsix rats each were fed three experimental diets containing approximately0%, 15%, and 30% of trans fatty acids but containing the same proportionof linoleic (18:2 n-6) and a-linolenic (18:3 n-3) acids for 10 wk. On d20 of pregnancy, the animals from each group were killed. We determinedthe fatty acid profiles in plasma, brain, and liver microsomes of pregnantrats, as well as in placenta and fetal liver and brain. No changes werefound in the number of fetuses of the pregnant rats. Trans fatty acidswere incorporated in high concentrations in placenta and in maternal andfetal tissues, except brain, strongly elevating the linoleic acid proportionand lowering that of docosahexaenoic acid. The delta-6 fatty-acid desaturaseactivity in the liver microsomes of the pregnant rats was inhibited bytrans isomers. In conclusion, high intakes of trans fatty acids partiallyinhibit liver delta-6 fatty-acid desaturase in pregnant rats, which mayexplain, in part, the low concentrations of docosahexaenoic acid in pregnantand fetal tissues. However, the fatty acid composition of both fetal andpregnant rat brain remains mostly unaffected regardless of the dietarytrans fatty acid content. PMID: 10674359, UI: 20136824 　 　

Docosahexaenoic acid (DHA), a major component of membrane phospholipidsin brain and retina, is profoundly reduced in patients with peroxisomebiogenesis disorders (Zellweger syndrome). Supplementing newborn patientswith DHA resulted in improved muscular tone and visual functions. The purposeof this study was to investigate (a) whether DHA levels were also reducedin newborn PEX5 knockout mice, the mouse model of Zellweger syndrome thatwe recently generated; (b) whether these levels could be normalized bysupplying DHA; and (c) whether this results in longer survival. The DHAconcentration in brain of newborn PEX5-/- mice was reduced by 40% as comparedwith levels in normal littermates; in liver, no differences were noticed.The daily administration of 10 mg of DHA-ethyl ester (EE) to pregnant heterozygousmothers during the last 8 days of gestation resulted in a normalizationof brain DHA levels in Zellweger pups. However, no clinical improvementwas observed in these pups, and the neuronal migration defect was unaltered.These data suggest that the accretion of DHA in the brain at the end ofembryonic development is not only supported by the maternal supply butalso depends on synthesis in the fetal brain. Furthermore, the DHA deficitdoes not seem to be a major pathogenic factor in the newborn Zellwegermice. PMID: 10653000, UI: 20116701 　 　

The age-related impairment in long-term potentiation in therat dentate gyrus is coupled with an increase in the proinflammatory cytokine,interleukin-1beta (IL-1beta). It is possible that this increase in IL-1betamight be a consequence of the age-related increase in reactive oxygen speciesproduction in hippocampal tissue. In this study we set out to identifythe underlying cause of the age-related increase in reactive oxygen speciesproduction and to establish whether any consequences of such a change mightimpact on the ability of aged rats to sustain long-term potentiation (LTP).We report that there was an age-related increase in the activity of superoxidedismutase but no parallel increases in activities of glutathione peroxidaseor catalase, while age-related decreases in the concentration of the scavengers,vitamins E and C and glutathione were also observed. We propose that thesecompromises in antioxidative strategies may result in an increase in reactiveoxygen species production. The data described indicate that IL-1beta andH2O2 increase the activity of two stress-activated mitogen-activated proteinkinases, c-Jun NH2-terminal kinase (JNK) and p38 in vitro, while age-relatedincreases in both kinases were observed. We propose that the endogenousincrease in these parameters which occurs with age induces the increasein activity of the stress-activated kinases, which in turn impacts on theability of the aged rat to sustain LTP. PMID: 10651889, UI: 20117571 　　

Recent research suggests that deficient uptake or excessivebreakdown of membrane phospholipids may be associated with schizophrenia.We review available clinical research on abnormalities in membrane fattyacid composition and metabolism in schizophrenia, and therapeutic trialsof fatty acid in this disorder. All potentially relevant English-languagearticles were identified from the medical and psychiatric literature withthe aid of computer searches using key words such as lipids, phospholipids,prostaglandins and schizophrenia. All studies which include human subjectsare reviewed. Empirical studies related to membrane hypotheses of schizophreniafocus on: 1) assessment of prostaglandins (PG) and their essential fattyacid (EFA) precursors in the tissues of patients with schizophrenia; 2)evaluation of the niacin flush test as a possible diagnostic marker; 3)evaluation of phospholipase enzyme activity; 4) NMR spectroscopy studiesof brain phospholipid metabolism; and 5) therapeutic trials of PG precursorsfor the treatment of schizophrenia. The most consistent clinical findingsinclude red blood cell fatty acid membrane abnormalities, NMR spectroscopyevidence of increased phospholipid turnover and a therapeutic effect ofomega-3 fatty acid supplementation of neuroleptic treatment in some schizophreniapatients. Studies of EFA metabolism have proved fruitful for generatingand testing novel etiologic hypotheses and new therapeutic agents for schizophrenia.Greater attention to factors that influence tissue EFA levels such as diet,tobacco and alcohol are required to reconcile inconsistent findings. Treatmentstudies, although promising, require independent replication. PublicationTypes: Review Review, tutorial PMID: 10650444, UI: 20116224 　 　

We studied the effects of a diet chronically deficient in alpha-linolenicacid, the precursor of long-chain n-3 polyunsaturated fatty acids, on dopaminergicneurotransmission in the shell region of the nucleus accumbens of rats.In vivo microdialysis experiments showed increased basal levels of dopamineand decreased basal levels of metabolites, 3,4-dihydroxyphenylacetic acid(DOPAC) and homovanillic acid (HVA), in awake rats from the deficient groupcompared to controls. The release of dopamine under KCl stimulation wassimilar in both dietary groups. By contrast, the release of dopamine fromthe vesicular storage pool under tyramine stimulation was 90% lower inthe deficient than in the control rats. Autoradiographic studies in thesame cerebral region revealed a 60% reduction in the vesicular monoaminetransporter sites in the deficient group. Dopamine D(2) receptors were35% increased in these rats compared to controls, whereas no change occurredfor D(1) receptors and membrane dopamine transporters. These results demonstratedthat chronic n-3 polyunsaturated fatty acid deficiency modifies severalfactors of dopaminergic neurotransmission in the nucleus accumbens. Thesefindings are in agreement with the changes in dopaminergic neurotransmissionalready observed in the frontal cortex, and with the behavioral disturbancesdescribed in these deficient rats. PMID: 10627499, UI: 20094871 　 　

Generalized peroxisomal disorders are severe congenital diseasesthat involve the central nervous system, leading to severe psychomotorretardation, retinopathy, liver disease, and early death. In these disorders,peroxisomes are not normally formed and their enzymes are deficient. Characteristically,plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids(VLCFAs) are affected. We found that patients with generalized peroxisomaldisorders have a profound brain deficiency of docosahexaenoic acid (DHA;22:6n-3) and low DHA concentrations in all tissues and the blood. Giventhe fundamental role of DHA in neuronal and retinal membranes, a DHA deficiencyof this magnitude might be pathogenic. Thus, we studied the possible therapeuticeffect of normalizing DHA concentrations in patients with peroxisomal disorders.We chose the DHA ethyl ester (DHA-EE) because of its high degree of purityat daily oral doses of 100-500 mg. This article summarizes the resultsof treatment of 13 patients with DHA-EE, with some follow-up evidence ofclinical improvement. Supplementation with DHA-EE normalized blood DHAvalues within a few weeks. Plasmalogen concentrations increased in erythrocytesin most patients and after DHA concentrations were normalized, amountsof VLCFAs decreased in plasma. Liver enzymes returned almost to normalin most cases. From a clinical viewpoint, most patients showed improvementin vision, liver function, muscle tone, and social contact. In 3 patients,normalization of brain myelin was detected by magnetic resonance imaging.In 3 others, myelination improved. In a seventh patient, myelination isprogressing at a normal rate. These results suggest a fundamental roleof DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus stronglyrecommended, not only to alleviate symptoms in patients with life-threateningdiseases, but also to clarify remaining questions regarding the role ofDHA in health and disease. PMID: 10618001, UI: 20084805 　 　

Dyslexia is a widespread condition characterized by difficultywith learning and movement skills. It is frequently comorbid with dyspraxia(developmental coordination disorder), the chief characteristic of whichis impaired movement skills, indicating that there may be some common biologicalbasis to the conditions. Visual and central processing deficits have beenfound. The long-chain polyunsaturated fatty acids (LCPUFAs) are importantcomponents of retinal and brain membranes. In the preliminary studies reportedhere, dark adaptation was shown to be impaired in 10 dyslexic young adultswhen compared with a similar control group (P < 0.05, repeated-measuresanalysis of variance); dark adaptation improved in 5 dyslexia patientsafter supplementation with a docosahexaenoic acid (DHA)-rich fish oil for1 mo (P < 0.05, paired t test on final rod threshold); and movementskills in a group of 15 dyspraxic children improved after 4 mo of supplementationwith a mixture of high-DHA fish oil, evening primrose oil, and thyme oil(P < 0.007 for manual dexterity, P < 0.02 for ball skills, and P< 0.03 for static and dynamic balance; paired t tests). The studieswere small and had designs that did not allow firm conclusions to be made.However, when considered with other evidence from another closely relatedcondition, attention-deficit hyperactivity disorder, for which reducedability to elongate and desaturate the essential fatty acids linoleic acidand alpha-linolenic acid to arachidonic acid and DHA, respectively, hasbeen proposed, the studies suggest that more research, including double-blind,placebo-controlled studies, would be useful to clarify the benefits ofLCPUFAs in dyslexia and other closely related conditions. PMID: 10617990,UI: 20084794 　 　

Growth cones are membrane-rich structures found at the distalend of growing axons and are the predecessors of the synaptic membranesof nerve endings. This study examined whether n-3 fatty acid restrictionduring gestation in rats alters the composition of growth cone and neuronalcell body membrane fatty acids in newborns. Female rats were fed a standardcontrol diet containing soy oil (8% of fatty acids as 18:3n-3 by wt) ora semisynthetic n-3 fatty acid-deficient diet with safflower oil (0.3%of fatty acids as 18:3n-3 by wt) throughout normal pregnancy. Experimentswere conducted on postnatal day 2 to minimize the potential for contaminationfrom synaptic membranes and glial cells. Dietary n-3 fatty acid restrictionresulted in lower docosahexaenoic acid (DHA) concentrations and a correspondinghigher docosapentaenoic acid concentration in neuronal growth cones, buthad no effects on neuronal cell body fatty acid concentrations. These studiessuggest that accretion of DHA in growth cones, but not neuronal cell bodies,is affected by n-3 fatty acid restriction during gestation. Differencesin other fatty acids or components between the semisynthetic and the standarddiet, however, could have been involved in the effects on growth-cone DHAcontent. The results also provide evidence to suggest that the additionof new membrane fatty acids to neurons during development occurs alongthe shaft of the axon or at the growth cone, rather than originating atthe cell body. PMID: 10617988, UI: 20084792 　 　

Arachidonic (AA) and docosahexaenoic (DHA) acids are majorcomponents of cell membranes and are of special importance to the brainand blood vessels. In utero, the placenta selectively and substantiallyextracts AA and DHA from the mother and enriches the fetal circulation.Studies indicate that there is little placental conversion of the parentessential fatty acids to AA and DHA. Similarly, analyses of desaturationand reductase activity have shown the placenta to be less functional thanthe maternal or fetal livers. There appears to be a correlation with placentalsize and plasma AA and DHA proportions in cord blood; therefore, placentaldevelopment may be an important variable in determining nutrient transferto the fetus and, hence, fetal growth itself. In preterm infants, bothparenteral and enteral feeding methods are modeled on term breast milk.Consequently, there is a rapid decline of the plasma proportions of AAand DHA to one quarter or one third of the intrauterine amounts that wouldhave been delivered by the placenta. Simultaneously, the proportion oflinoleic acid, the precursor for AA, rises in the plasma phosphoglycerides3-fold. An inadequate supply of AA and DHA during the period of high demandfrom rapid vascular and brain growth could lead to fragility, leakage,and membrane breakdown. Such breakdown would predictably be followed byperoxidation of free AA, vasoconstriction, inflammation, and ischemia withits biological sequelae. In the brain, cell death would be an extreme consequence.Publication Types: Review Review, tutorial PMID: 10617983, UI: 20084787　 　

Domains of behavior may be broadly categorized as sensory,motor, motivational and arousal, cognitive, and social. Differences inthese domains occur because of changes in brain structure and function.Docosahexaenoic acid (DHA; 22:6-23) and arachidonic acid (AA; 20:4-26)are major structural components of the brain that decrease when diets deficientin the essential fatty acids (EFA) alpha-linolenic acid and linoleic acidare consumed. Early electrophysiologic and behavioral studies in EFA-deficientrodents showed behavioral effects attributable to lower-than-normal accumulationof DHA and AA in the brain. More recently, electrophysiologic and behavioralstudies in EFA-deficient primate infants and analogous studies in humaninfants have been conducted. The human infants were fed formulas that couldresult in lower-than-optimal accumulation of long-chain polyunsaturatedfatty acids (LCPUFAs) in the brain during critical periods of development.This article describes the behavioral methods that have been used to studyprimate infants. These methods may be unfamiliar to many physicians andnutritionists who wish to read and interpret the human studies. The behavioraloutcomes that have been evaluated in LCPUFA studies represent only a fractionof those available in the behavioral sciences. Specific developmental domainshave been studied less often than global development, even though studiesof nonhuman primates deficient in EFAs suggest that the former providemore information that could help target the underlying mechanisms of actionof LCPUFAs in the brain. Publication Types: Review Review, tutorial PMID:10617982, UI: 20084786 　 　

The interest in factors that modify early infant developmenthas led investigators to focus on n-3 and n-6 long-chain polyunsaturatedfatty acids (LCPUFAs) in the past 2 decades. The presence of docosahexaenoicacid (DHA) and arachidonic acid (AA) in breast milk, compared with theirabsence from infant formulas available in the United States, has promptedclinical trials designed to examine whether LCPUFA enrichment of infantformula has beneficial effects on maturational events of the visual system.These trials have shown significant functional advantages of LCPUFA supplementationfor preterm infants, whereas benefits for full-term infants remain controversial.The growth and safety of preterm infants was not compromised by LCPUFAenrichment, although these issues remain to be resolved in clinical trialswith full-term infants. Publication Types: Review Review, tutorial PMID:10617979, UI: 20084783 　 　

Animal studies have been of pivotal importance in advancingknowledge of the metabolism and roles of n-6 and n-3 fatty acids and theeffects of specific dietary intakes on membrane composition and relatedfunctions. Advantages of animal studies include the rigid control of fattyacid and other nutrient intakes and the degree, timing, and duration ofdeficiency or excess, the absence of confounding environmental and clinicalvariables, and the tissue analysis and testing procedures that cannot beperformed in human studies. However, differences among species in nutrientrequirements and metabolism and the severity and duration of the dietarytreatment must be considered before extrapolating results to humans. Studiesin rodents and nonhuman primates fed diets severely deficient in alpha-linolenicacid (18:3n-3) showed altered visual function and behavioral problems,and played a fundamental role by identifying neural systems that may besensitive to dietary n-3 fatty acid intakes; this information has assistedresearchers in planning clinical studies. However, whereas animal studieshave focused mainly on 18:3n-3 deficiency, there is considerable clinicalinterest in docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6)supplementation. Information from animal studies suggests that brain andretinal concentrations of 22:6n-3 plateau with 18:3n-3 intakes of approximately0.7% of energy, but this requirement is influenced by dietary 18:2n-6 intake.Blood and tissue concentrations of 22:6n-3 increase as 22:6n-3 intake increases,with adverse effects on growth and function at high intakes. Animal studiescan provide important information on the mechanisms of both beneficialand adverse effects and the pathways of brain 22:6n-3 uptake. PublicationTypes: Review Review, tutorial PMID: 10617978, UI: 20084782 　 　

In animal feeding studies, and probably in humans, n-3 polyunsaturatedfatty acids (PUFAs) prevent fatal ischemia-induced cardiac arrhythmias.We showed that n-3 PUFAs also prevented such arrhythmias in surgicallyprepared, conscious, exercising dogs. The mechanism of the antiarrhythmicaction of n-3 PUFAs has been studied in spontaneously contracting culturedcardiac myocytes of neonatal rats. Adding arrhythmogenic toxins (eg, ouabain,high Ca(2+), lysophosphatidylcholine, beta-adrenergic agonist, acylcarnitine,and the Ca(2+) ionophore) to the myocyte perfusate caused tachycardia,contracture, and fibrillation of the cultured myocytes. Adding eicosapentaenoicacid (EPA: 5-15 micromol/L) to the superfusate before adding the toxinsprevented the expected tachyarrhythmias. If the arrhythmias were firstinduced, adding the EPA to the superfusate terminated the arrhythmias.This antiarrhythmic action occurred with dietary n-3 and n-6 PUFAs; saturatedfatty acids and the monounsaturated oleic acid induced no such action.Arachidonic acid (AA; 20:4n-6) is anomalous because in one-third of thetests it provoked severe arrhythmias, which were found to result from cyclooxygenasemetabolites of AA. When cyclooxygenase inhibitors were added with the AA,the antiarrhythmic effect was like those of EPA and DHA. The action ofthe n-3 and n-6 PUFAs is to stabilize electrically every myocyte in theheart by increasing the electrical stimulus required to elicit an actionpotential by approximately 50% and prolonging the relative refractory timeby approximately 150%. These electrophysiologic effects result from anaction of the free PUFAs to modulate sodium and calcium currents in themyocytes. The PUFAs also modulate sodium and calcium channels and haveanticonvulsant activity in brain cells. Publication Types: Review Review,tutorial PMID: 10617972, UI: 20084776 　 　

In the past 2 decades, views about dietary n-3 fatty acidshave moved from speculation about their functions to solid evidence thatthey are not only essential nutrients but also may favorably modulate manydiseases. Docosahexaenoic acid (22:6n-3), which is a vital component ofthe phospholipids of cellular membranes, especially in the brain and retina,is necessary for their proper functioning. n-3 Fatty acids favorably affectatherosclerosis, coronary heart disease, inflammatory disease, and perhapseven behavioral disorders. The 38 articles in this supplement documentthe importance of n-3 fatty acids in both health and disease. PublicationTypes: Review Review, tutorial PMID: 10617967, UI: 20084771