Of all organs in the human body (excluding adipose tissue), the nervous system has the highest lipid content. The dry weight of an adult brain is 50% to 60% lipid, and 35% of the lipid content is accounted for by PUFAs (1) (See Table 1 for a list of abbreviations used in this paper). AA and DHA, which contain 20 and 22 carbons, respectively, appear in the highest concentrations (2,3).
DHA, a key omega-3 acid, is especially important during prenatal human brain development: it is incorporated into nerve growth cones in events leading to synaptogenesis (4,5). Jones and coworkers have recently presented evidence that DHA is involved in cholinergic synaptic transmission (6). The brain growth spurt that takes place from the third trimester of pregnancy until 18 months after birth also correlates well with DHA accretion in brain phospholipids (7,8). Nature makes doubly sure that the infant brain is provided with the necessary LC-PUFAs: both the placenta (9) and breast feeding (10,11) supply predominantly DHA and AA to the growing young. DHA deficiency can have marked consequences, including retarded visual acuity (11), cognitive impairment (12), cerebellar dysfunction (13), and various other neurological disorders (14).
Providing a persuasive historical backdrop for this topic, Chamberlain (15) and Broadhurst and others (16) have proposed the necessity of LC-PUFAs for human intellectual evolution. Their reviews correlate the marked enlargement of the hominid cerebral cortex during the last 2 million years (when the genus Australopithecus died out and the Homo species emerged) with a relatively high dietary fish intake. The numerous freshwater lakes in the Rift Valley in Eastern Africa, where early hominid development took place, provided a diet rich in LC-PUFAs.
This review aims, first, to explain briefly why the structure of highly unsaturated fatty acids enables them to play such an important role in brain cell membranes. The possible role of PUFAs in neurotransmission, gathered from in vitro and in vivo animal experiments, is described. Finally, PUFA supplementation studies in human cohorts with various psychiatric conditions are reviewed.
This review was presented in 2001, at the University of Pretoria, as a lecture to introduce postgraduate medical students in psychiatry to the field. Material was gathered by searching Medline databases for articles using the following key words: polyunsaturated fatty acids, essential fatty acids, omega-3 fatty acids, docosahexanoic acid, eicosapentanoic acid, arachidonic acid, neurotransmission, phospholipase A2, depression, schizophrenia, mental performance, attention- deficit hyperactivity disorder, and Alzheimer’s disease. Biochemistry textbooks were consulted on the role of fatty acids in membrane function, neurotransmission, and eicosanoid formation.
PUFA Synthesis and Structure
LC-PUFAs cannot be formed de novo but can be synthesized from the essential fatty acids LA and ALA, as illustrated in Figure 1. LA is the parent compound of the so-called omega-6 family of fatty acids, as is ALA of the omega-3 family. These parent fatty acids are desaturated and lengthened progressively by microsomal enzyme systems (17) to form the important, highly unsaturated, long-chained AA and DHA. Members of the 2 families are not interconvertible. They also compete for the same enzyme systems.
Fatty Acids Can Be Kinked
Figure 1 PUFA synthesis from parent essential fatty acids
LA: linoleic acid; GLA: gamma-linolinolenic acid; DGLA: dihomogammalinolenic acid; AA: arachidonic acid; ALA: alpha-linolenic acid; EPA: eicosapentanoic acid. In the shorthand notation used here, the first number denotes the number of carbon atoms in the fatty acid molecule, and the number after the colon denotes the number of double bonds it contains.
Membrane Phospholipid Turnover
The cell membrane is in a constant state of flux: fatty acids are released from the membrane by phospholipases (Figure 3). PLA2 can release AA, DGLA, and EPA from the sn-2 position of membrane phospholipids, but with vastly differing consequences: DGLA and AA (both omega-6), as well as EPA (omega-3), can be transformed into prostaglandins and thromboxanes of the 1-, 2-, and 3-class, respectively. The 2-class is highly proinflammatory, and the 1-class has intermediate properties, whereas the 3-class is antiinflammatory. It has been hypothesized that a highly reactive PLA2 is found in various psychiatric disorders (24,25). When coupled with a high omega-6 PUFA content in the cell membrane, it would thus lead to aggravated inflammatory conditions. This would, of course, be limited by the presence of sufficient omega-3 fatty acids in the membrane.
Fatty Acids and Signalling Pathways in the Nervous System
PUFAs can modulate many of the signal transduction mechanisms operating in neuronal membranes and, thus, in the synaptic cleft. Figure 4 presents the most important membrane second-messenger mechanisms. (The shaded dots show loci where PUFA effects have been demonstrated). Various neurotransmitters—for example, serotonin, the catecholamines, and acetylcholine (26–28)—interact with members of a heptahelical transmembrane receptor family. G proteins linked to these receptors transduce their signals; the role of DHA in this regard has recently been discussed by Salem and others (29).
AC drives the cAMP messenger system. This pathway is used by 5-HT1 (serotonin) receptors, alpha-2 and beta-adrenergic (noradrenaline and adrenaline) receptors, and both D1 and D2 (dopamine) receptors. PUFAs can influence this pathway at 2 points: they can increase both AC (30,31) and PKA (32) activity. Conversely, PLC starts the phosphoinositide signalling pathway, where PUFAs can exert their effects on PLC (33) and PKC (34)—both of which are involved in 5-HT2 and alpha-1 adrenergic transmission. The 2 other membrane phospholipases, D and A2, are also affected by PUFAs (35–37) and play an important role in neurotransmission. PLA2 can be activated by dopamine D2 receptors (38), serotonin 5-HT2 receptors (39), glutamate receptors (40), and muscarinic acetylcholine receptors (41). PLA2 liberates fatty acids from the sn-2 position of phospholipids, and these can subsequently be used as precursors for prostaglandins, thromboxanes, lipoxins, and leukotrienes. These eicosanoids themselves can have many effects on signal tranduction (42). The different effects of prostaglandins could be caused by the different signalling systems they use: prostaglandins of the 2 family transduce signals via a Gs protein, thus elevating cAMP levels, whereas those of the 3 family use a Gi protein, which has the opposite effect. Prostaglandins of the 1 family use a phosphoinositide signalling system (43).
PUFAs can also modulate ion channels (for example those for Ca2+ and Na+) (44,45). Further events in the process of neurotransmission, and eventual release of neurotransmitters from synaptic vesicles, are ushered in by activation of Ca2+-CM-PKs; here also, PUFA effects have been noted (46). The thousandfold concentration gradient between extra- and intracellular Ca2+ is maintained by Ca-ATPase in neuronal membranes: Kearns and Haag have recently noted an inhibition of this enzyme by both DHA and EPA (47).
Figure 2 Atomic molecular models of selected essential fatty acids
Figure 3 Role of PUFAs in signal transduction
1: Gs protein; 2: adenylate cyclase; 3: protein kinase A; 4: Gp protein; 5: phospholipase C; 6: protein kinase C; 7: tyrosine kinase; 8: ion channel; 9: phospholipase A2; AA: arachidonic acid; DGLA: dihomogammalinolenic acid; EPA: eicosapentanoic acid; PL: phospholipid; PIP2: phosphatidylinositol pyrophosphate; DAG: diacyl glycerol; ER: endoplasmic reticulum; IP3 and IP4: inositoltris- and tetrakisphosphates.
Figure 4 Membrane phospholipid turnover
PLA2 (Phospholipase A2) hydrolyses phospholipids in the cell membrane, forming fatty acids which are precursors of eicosanoids. CoAIT (Coenzyme A-independent transacylase) and ACLAT (Acyl-coenzyme A: lyso-phospholipid acyltransferase) replenish fatty acids in membrane phospholipids. AA: arachidonic acid; DGLA: dihomogammalinolenic acid; EPA: eicosapentanoic acid; COX: cyclo-oxygenase; FA: fatty acid; LO: lipoxygenase.
PUFA Supplementation in Animal and Human Models
Dietary Supplementation in Experimental Animals
Subsequent studies by Delion and colleagues (48,49) compared peanut oil supplementation in a diet deficient in omega-3 with peanut plus rapeseed oil supplementation in a diet with adequate omega-3. They reported a lower density of D2 receptors and lower dopamine levels in the cerebral cortex of the omega-3–deprived group, coupled with increased serotonin levels and 5-HT2 receptor density, accompanied by a low ratio of omega-3 to omega-6 PUFA content in the membrane. Driving this line of investigation still further, Chalon and coworkers increased the ratio of omega-3 to omega-6 PUFA by using fish oil plus palm oil in the diet (50). This resulted in increased dopamine receptors as well as increased dopamine levels in the cerebral cortex. By contrast, however, this dietary strategy also decreased both ambulatory activity and dopamine binding in the striatum. Reporting from the same laboratory, Zimmer and others showed that dopamine breakdown was higher in omega-3–deficient rats than in control rats and proposed that the internalization of dopamine in the storage pool of the cerebral cortex was modified in the omega-3–deprived group (51,52). Recently, De la Presa Owens and Innis (53) have also published evidence showing that PUFA-deprived rats have higher dopamine and serotonin levels in the frontal cortex than do control rats. Unfortunately, however, this study does not allow differentiation between the effects of omega-3 and omega-6 PUFAs.
Researching the influence of omega-3 PUFA deprivation on learning, Okuyama (54) and colleagues compared rats fed safflower oil (which is omega-3 deficient) with rats fed perilla oil (which is omega-3 adequate). They demonstrated that the rats fed safflower oil showed inferior learning ability (according to the brightness discrimination test) and a 30% decreased synaptic vesicle density in the hippocampal CA1 region. Okuyama and colleagues also reported increased hippocampal acetylcholine levels and improved passive avoidance in stroke-prone, spontaneously hypertensive rats supplemented with DHA (55).
PUFA Intervention Trials in Human Subjects
Attention-Deficit Hyperactivity Disorder (ADHD). ADHD has also been linked to LC-PUFA deficiency: a low serum ratio of omega-3 to omega-6 PUFA, coupled with a possible delta-6-desaturase deficit, has been reported in boys with this condition (66). However, a recent randomized double-blind placebo-controlled trial could not improve the symptoms of ADHD, although higher plasma DHA levels were attained with a regime of omega-3 supplementation (67).
Psychological Stress. Looking for possible protective effects of PUFAs in psychological stress, Maes and coworkers recently surveyed a sample of students, measuring levels of proinflammatory cytokines (IFN-gamma, TNF-alpha, IL-5, and IL-6) both before and after a difficult oral examination. These levels were correlated with the serum ratio of omega-3 to omega-6; a low ratio of omega-3 to omega-6 predisposed subjects to higher rises in cytokine production during stress (68).
Depression. Twenty years ago, Horrobin and Manku had already noted the possible causative role of prostaglandins and their parent fatty acids in depression (69). In 1995, Hibbeln and Salem (70) proposed a link between the marked increase in depression rates in the 20th century (71) and increased intake of PUFAs containing omega-6 in the form of plant oils. The 1996 report of Adams and coworkers supported this hypothesis (72). These researchers showed a significant positive correlation in 20 subjects between depression severity (measured according to the Hamilton Depression Rating Scale as well as a linear scale that omits anxiety) and the ratio of AA (omega-6) to EPA (omega-3) in erythrocyte phospholipids. In a similar vein, Edwards and others reported a significant depletion of omega-3 PUFAs in the red blood cell membranes of 10 subjects with a diagnosis of a major depressive episode according to DSM-IV criteria, compared with matched normal control subjects (73). This study rated participants according to the Beck Depression Inventory and controlled fully for possible confounders such as diet, smoking, and stress. Maes and colleagues have since also reported trials with similar results (74,75). Pursuing the possibility that omega-3 fatty acids may reduce vulnerability to depression, Stoll and coworkers reported a trial in which fish-oil supplementation, albeit in relatively high dosages, had beneficial effects in treating patients with bipolar disorder during their depressive phases (76). In contrast to the foregoing results, 2 early studies (77,78) demonstrated increased EPA and DHA in erythrocyte membranes of a mixed group of patients with bipolar affective disorder and reactive or mild depression. The discrepancy in these results may be owing to the fact that the subjects in these trials were not selected by as strict diagnostic criteria as were subjects in the later trials.
Schizophrenia. Mellor and colleagues have conducted trials investigating phospholipid abnormalities in schizophrenia patients. Twenty subjects with chronic schizophrenia (according to DSM-III-R criteria) and taking neuroleptic medication showed decreased ratios of omega-3 to omega-6 in red blood cell membranes. This abnormality was also found in their brain tissue post mortem. Fish-oil supplementation of 10 g daily did, however, ameliorate the symptoms of surviving patients, according to their total Positive and Negative Syndrome Scale and Abnormal Involuntary Movement Scale scores (79,80). These results are corroborated by Yao and others (81,82). However, all these studies are difficult to interpret, since in most cases patients have already received some form of medication that could influence the outcome. A case in point is the most recent report by Peet and others (83). Their study could only show important and statistically significant beneficial effects of 2 g daily EPA in the presence of clozapine, while their placebo group receiving antipsychotics alone also showed a positive response. Further, Fenton and others, researching a relatively large cohort of 75 subjects with schizophrenia, could find no effect of 3 g daily ethyl-EPA on all ratings measured (84). As stated in a recent review by Joy and others (85), more results are urgently needed before fish oil or ethyl-EPA can be regarded as beneficial in the treatment of schizophrenia.
Multiple Sclerosis (MS). Dietary fat has been implicated in the etiology of MS since the early 1950s. An early Norwegian study showed a lower incidence of MS in coastal communities with a high fish intake, compared with inland rural communities where consumption of saturated fat is higher (86). Thus, a shortage of dietary PUFAs may be a risk factor in MS. Indeed, later studies found decreased levels of both omega-3 and omega-6 PUFAs in red blood cells, plasma, and adipose tissue of patients diagnosed with MS (87). Because MS is associated with an activated inflammatory response and omega-3 highly unsaturated fatty acids can suppress IFN, IL, and TNF production in MS subjects (88), treatment with omega-3 fatty acids seems to have a reasonable theoretical basis. In 2000, Nordvik and others reported a study in which 16 newly diagnosed MS patients were treated with 0.9 g EPA plus DHA daily (89). In addition, they were given dietary advice. After 2 years, there was a reduction in the mean annual exacerbation rate and the mean Expanded Disability Status Scale, compared with their status before the study. Conversely, a study of 195 new cases of MS, undertaken by Zhang and others and also published in 2000, could show no difference from any type of dietary fat intake between MS patients and control subjects (90).
Alzheimer’s Disease and Huntington’s Chorea. The normal aging process is characterized by decreased delta-6- desaturase activity (91,92), increased inflammatory response (93), and oxidative damage to the cell membrane (94). Lynch and colleagues have recently reported that, in rats, EPA can prevent oxidative stress triggered by apoptotic cell death in the hippocampus (95). They have also shown that age-related decreases in long-term potentiation and glutamate release can be reversed by omega-3 supplementation (96). In a study by Yehuda and coworkers (97), symptoms of Alzheimer’s disease, such as short-term memory loss, depressed mood, and inability to sleep (symptoms often found in the elderly), were markedly ameliorated by treatment with SR-3 (an essential fatty acid preparation containing omega-3). Thus, PUFAs may well be used clinically. For a small cohort of 8 patients suffering from end-stage Huntington’s disease, ethyl-EPA at a dosage of 2g daily was also beneficial in treating the orofacial abnormalities associated with this condition (98).
Increasing evidence shows that a correct balance between omega-3 and omega-6 fatty acids in brain cell membranes is important to mental health. This paper has reviewed some clinical evidence that higher dosages of omega-3 fatty acids (2 to 4g daily) may ameliorate the symptoms of several psychiatric conditions. However, more data are required to reach conclusive answers in this regard. DHA and AA play the most important role in nerve function: they are long, highly unsaturated fatty acids from the omega-3 and omega-6 fatty acid families. (The role of the longest omega-6 fatty acid, DPA [22:5], in cell membrane function still needs to be ascertained.) The current Western diet does not supply omega-3 and omega-6 fatty acids in the desired proportion (1:4). In the UK and Western Europe, the ratio is as low as 1:15 (99). It is important that the public, dieticians, the medical profession, and policy-makers in charge of nutrition programs be conscious of this recommendation and work toward ensuring an adequate daily DHA-plus-EPA intake by the population.
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Manuscript received August 2002, revised, and accepted December 2002.
1. Associate Professor, Department of Physiology, University of Pretoria, Pretoria, South Africa.
Address for correspondence: Prof M Haag, Department of Physiology, University of Pretoria, PO Box 2034, Pretoria 0001, South Africa
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