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3 Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada C1A 4P3; and 4 Amarin Neuroscience/Laxdale Ltd, Oxford, UK OX4 4GA
* To whom correspondence should be addressed. E-mail: cai.song{at}nrc.gc.ca.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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-linolenic acid (GLA), and arachidonic acid (AA) modulate neurotransmitters, behavior, and brain inflammation were evaluated in rats that received central saline or interleukin-1β (IL-1) administrations. In rats treated with saline, only the AA-enriched diet significantly increased anxiety-like behavior in the elevated plus maze, which was associated with increased corticosterone secretion. AA also increased the turnover of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in the amygdala and increased the prostaglandin (PG)E2 level in the hippocampus. IL-1 administration slowed rat learning in the water maze and increased anxiety-like behavior, changes which were associated with increased homovanillic acid and 5-HT turnover, decreased NA in the hippocampus and amygdala, decreased DA in the frontal cortex, and decreased IL-10 in limbic brain regions. Increased corticosterone secretion following IL-1 administration was accompanied by increased NA turnover in the hippocampus (P < 0.05) and increased PGE2 concentration (P < 0.01) in the limbic brain regions. Of the 3 diets tested, only EPA attenuated IL-1–induced behavioral changes (P < 0.05 or 0.01), which was associated with the modulation of EPA on the neuroendocrine and immune changes induced by IL-1. GLA reduced hippocampal PGE2 concentration in rats given IL-1 (P < 0.01). AA did not counteract any of the changes induced by IL-1. These results suggest that EPA, GLA, and AA play different roles in the neuroendocrine-immune network.
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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-linolenic acid (GLA)6 and arachidonic acid (AA) and the (n-3) series includes eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The (n-3) and (n-6) fatty acids have different functions in the immune and central nervous systems and may antagonize and agonize each other (1). An imbalance of the membrane contents of these fatty acids resulting from dietary deficiency, aging, and diseases may cause abnormalities in neurotransmission and inflammatory responses by changing membrane fluidity, lipid peroxidation, eicosanoid production, and gene expression (1–4). Indeed, an increased (n-6):(n-3) fatty acids ratio and decreased (n-3) fatty acids concentration have been found in patients with neurodegenerative or inflammatory disorders (4–7). AA is the precursor of eicosanoids that produce prostaglandins (PG) and is also related to the synthesis of proinflammatory cytokines. Due to their ability to compete with AA (8) and thus inhibit the production of proinflammatory cytokines and PGE2, (n-3) fatty acids have been used to treat autoimmune diseases such as rheumatoid arthritis (9,10). Furthermore, evidence suggests that precursors or derivatives of (n-3) and (n-6) fatty acids may have different functions from their end products. For example, EPA, a precursor of DHA, can effectively treat depression and schizophrenia, whereas DHA does not have the same effect (4,6); GLA, a precursor of AA, can inhibit inflammatory response, but AA itself apparently cannot (11–13). Proinflammatory cytokines have recently been reported to modulate central nervous system functions and to contribute to many of the changes in psychiatric and neurodegenerative diseases (14–16). Interleukin-1β (IL-1) is a potent proinflammatory cytokine produced by macrophages and microglia. IL-1 receptors are widely distributed within the brain, with a high density in the hippocampus, amygdala, and hypothalamus (17,18). In rats, intracerebroventricular (i.c.v.) administration of IL-1 induces stress and anxiety-like behavior (19,20), memory impairment (21,22), and gene expression for β-amyloid precursor proteins (23); it can also trigger an inflammatory response (24–26) and change neurotransmission (27,28). Therefore, IL-1 administration to rodents has been used as a model for studying the interaction among inflammation, brain functions, and behavioral abnormalities.
Studies with rodents have also shown that (n-3) and (n-6) fatty acids differentially influence general behavior, anxiety-like behavior, and memory (29–31). Rats fed an (n-3) fatty acid-deficient diet had memory impairment and stress/aggressive behavior (3,30). Previously, we reported that IL-1–induced spatial memory deficit was attenuated in rats fed 1% EPA for 7 wk (21). Recently, we reported that 0.5% EPA, GLA, and AA differentially interact with IL-1 and modulate IL-1–induced anxiolytic behavior, peripheral immune function, and corticosterone secretion (20). However, the mechanisms underlying this at the neurotransmitter and neuroinflammatory levels are unknown. Therefore, the hypothesis of this study is that EPA, GLA, and AA will differentially modulate IL-1–induced changes in neurotransmitter synthesis and metabolism as well as brain inflammatory responses, which may be correlated with their effects on behaviors and corticosterone release.
To test this hypothesis, we studied the effects in rats of 4 different diets on spatial memory and anxiety-like behavior and on the concentrations of monoaminergic neurotransmitters and their metabolites in several brain regions, including the hippocampus, amygdala, frontal cortex, and hypothalamus, which are related to memory, emotion, fear, and neuroendocrine functions. Because IL-1–induced inflammatory response and glucocorticoid secretion in the brain occurs through the activation of PGE2 synthesis and its receptors (32) and because the antiinflammatory cytokine IL-10 produced by glial cells (33) may inhibit IL-1 effects, we also measured PGE2 and IL-10 concentrations in these brain regions. Because inflammatory disorders have been associated with several chronic psychiatric and neurodegenerative diseases, such as depression and Parkinson's disease, IL-1 was injected for 8 d.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Diets.
We used palm oil to ensure comparable texture and caloric values or as the control diet of fatty acids, because it contains very low amounts of linoleic aid, an (n-6) fatty acid, no (n-3) fatty acids, and no ethyl esters. Basal mix (Rx 991698, Harlan Teklad Test Diet) without fat was designed for use at 95% (950 g/kg) in preparing diets with the addition of 5% (50 g/kg) of a selected fat/oil. Ethyl-EPA (>95%), ethyl-GLA (>95%), and AA oil [containing 51% AA, 3% GLA, 15% 16:0, 12% (n-7) and (n-9), and 18% other non-(n-3) and (n-6) fatty acids] were from Amarin Neuroscience (nutrient compositions of diets in Table 1). The diet preparations, fatty acid concentrations, and feeding duration chosen in this study were the same as those used in our own and others' previous studies (20,34,35). Briefly, palm oil was mixed with basal mix followed by the addition of the appropriate concentrations of fatty acids. The food was prepared every 3–4 d and stored at 4°C. Rat daily intake of each diet was 
26 ± 3 g, which contained 0.13 g of each fatty acid. The feeding duration was 7 wk.
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IL-1 and i.c.v. injection. Rat recombinant IL-1 was obtained from NIBSC (biological activity, 317 IU/mg) and dissolved in sterile, pyrogen-free saline at doses of 15 ng in10 µL. The dose was based on those used in our previous study (5, 10, and 50 ng) and on other studies (10–20 ng) (37–39). The method for IL-1 injection was the same as previously described (21). In brief, rats were gently handled for 2 wk before the first injection. On the injection day, 10 µL IL-1 or saline was drawn into an internal needle that was connected to a micro-injector through a PE 50 polyethylene tube. IL-1 or saline was slowly infused into the brain over a period of 60 s. The injection needle was allowed to remain inside the guide cannula for 1 min (21).
Behavioral tests and procedure. The method used for training and testing rats in the Morris water maze was similar to that previously described (23). Briefly, the water tank was divided into 4 quadrants of equal size and designated as north (N), west (W), south (S), and east (E). Water temperature was maintained at 26 ± 1°C. One day before training, rats were singly placed into the pool of water without a platform and allowed to swim freely for 1 min (d 0). On d 1, a platform was positioned in 1 of the quadrants of the maze. Each rat was placed into the maze facing the wall at 1 of the 4 starting directions for 5 trials (N, W, S, E, and N). Rats were allowed to stay in the water for 60 s. Any rat that could not find the platform within 60 s was placed on the platform and allowed to stay there for 15 s. On d 2 and 3, rats were trained using the same procedure as on d 1. On d 4, the platform was relocated to a different quadrant of the maze. This training procedure was repeated on d 5. IL-1 or saline was injected into each animal immediately after trial 5 of training on each day. The swimming speed, path lengths, angles of swimming, and the latency to find the hidden platform were recorded every day using a video camera and computer system and analyzed using a computer (HVS IMAGE).
After water maze testing, rats were allowed to rest for 1 d while continuing to receive daily injections of IL-1 or saline. On d 7, rats were tested in an elevated plus maze. The apparatus consisted of an x-shaped maze elevated 1 m from the floor comprising 2 oppositely located enclosed and 2 open arms (21,40). On the day of testing, each rat was placed singly on the central square of the maze, facing the open arm (40). The entries into open and closed arms and the time spent on these arms were recorded during a 5-min observation period. Because IL-1 treatment may change animal locomotor activity in the maze, the ratio between the number of entries into open and closed arms and the ratio between time spent on open and closed arms were used as final results.
Brain dissection and neurotransmitter measurements. Fifty minutes after saline or IL-1β infusion on d 8, the rats were decapitated, their brains were rapidly removed, and the location of the cannulae and injection site were checked by slicing the brain coronally. Data were excluded for any rat in which the injection site failed to reach the lateral ventricle. After dissection, we weighed 4 brain regions (amygdala, hippocampus, frontal cortex, and hypothalamus) (41). Following sonication in an ice-cold buffer (500 mL contains L-ascorbic acid, 4.4 mg; 70% HClO4, 4.66 mL; EDTA, 50 mg), samples were centrifuged at 7000 x g for 25 min at 4°C. The concentration of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites or precursors 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan (Trp) were measured in the supernatants using HPLC with electrochemical detection (464-Water Millipore) as previously published (42).
Neurotransmitter results were expressed as the percentage of the mean obtained from the control group (SAL-PALM), i.e. a neurotransmitter or metabolite concentration in each sample including each control sample was divided by mean of controls and then multiplied by 100. The turnover of these monoamines was expressed as the ratios of MHPG:NA, DOPAC:DA, and 5-HIAA:5-HT based on their respective absolute concentrations in the brain.
Brain PEG2 and IL-10 assays. The concentrations of IL-10 and PGE2 were measured in the supernatants of the hippocampus, amygdala, and hypothalamus (after sonication) by a quantitative ELISA (Biosource International) and an enzyme immunoassay (Assay Designs), respectively, as described previously (21). Results are expressed as pg/g fresh brain tissue.
Corticosterone assay. Serum corticosterone concentrations were measured with a commercial radioimmunoassay kit (Immuchem corticosterone RIA kit for rats; catalog no. RCBK9906A; ICN Biochemical). The intra- and interassay CV were 6.8 and 5.6%, respectively.
Statistical methods. Behavioral results were analyzed by 2-way repeated measures ANOVA (saline/IL-1 x diet). Other results were analyzed by 2-way ANOVA. When main effects or interactions were significant, post hoc Newman-Keuls analysis was conducted (GB-STAT, Dynamic Microsystems). Differences were considered significant at P < 0.05. Results were expressed as means ± SEM.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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On d 0 of water maze training, swimming speed and path lengths and angles did not differ among the groups fed the 4 diets (results not shown). On d 1, these variables and the latency for locating the platform did not differ among the groups (Fig. 1A). On d 2, the diets did not affect these variables in rats administered saline (Fig. 1B). Similar results were found on d 3–5. However, IL-1 administration affected latency on d 2; IL1-PALM, IL1-GLA, and IL1-AA groups required a much longer time to find the platform in the water maze compared with the saline-injected controls (P < 0.01) (Fig. 1B). In contrast, latency was shorter in the IL1-EPA group than in the IL1-PALM group (P < 0.01) (Fig. 1B). IL-1 administration did not significantly affect other variables measured on d 2. On d 3, similar results were found; only EPA attenuated the IL-1-induced delay in the latency (P < 0.01) (Fig. 1C). On d 4, after platform relocation, all groups required a longer time to locate the platform, but the IL1-PALM, IL1-GLA, and IL1-AA groups still took a longer time than the saline-injected controls (P < 0.05). Only EPA shortened the IL-1–induced delay (P < 0.05) (Fig. 1D). On d 5, similar results to those on d 4 were found; IL1-PALM, IL1-GLA, and IL1-AA rats took a longer time to locate the platform than saline-treated rats fed the same diet (P < 0.05) even though all rats took less time to find the platform overall (Fig. 1E).
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Effects of diets on hippocampal neurotransmitters and metabolites. Saline-treated rats Compared with the SAL-PALM group, the EPA-enriched diet increased the concentration of DA (P < 0.01), DOPAC (P < 0.05), HVA (P < 0.01), and 5-HT (P < 0.05) without changing the ratio of DOPAC:DA (Table 2). The GLA-supplemented diet only increased the HVA concentration (P < 0.05). In the SAL-AA group, the DA concentration was higher than in the SAL-PALM group (P < 0.05). However, none of the 4 diets significantly affected the noradrenergic or serotonergic systems in this brain region (Table 2).
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Following IL-1 administration, the group fed palm oil had higher HVA concentrations (P < 0.01). IL-1 also interacted with the AA diet to increase the DA concentration (P < 0.01) (Table 2). The EPA- or GLA-supplemented diet did not affect IL-1–induced changes. A similar pattern was observed for DA metabolites HVA (P < 0.01) and DOPAC (P < 0.05) in this brain region of the IL1-AA group (Table 2). However, there was no change in the DOPAC:DA ratio (results not shown).
IL-1 administration induced a higher 5-HIAA concentration and 5-HIAA:5-HT ratio in the rats fed palm oil (P < 0.05 and P < 0.01, respectively) (Table 2). GLA or EPA significantly attenuated the change in the 5-HIAA:5-HT ratio (P < 0.01) (Table 2).
Effects of diets on amygdala neurotransmitters and metabolites. Saline-treated rats There was no dietary effect on NA and MHPG concentrations in the saline-treated groups. Diets enriched with AA significantly increased DA and 5-HT turnovers (P < 0.01) and increased the concentration of 5-HIAA (P < 0.05) but decreased Trp concentrations (P < 0.05). Other diets did not affect dopaminergic and serotonergic metabolism (Table 3).
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IL-1 administration did not affect the dopaminergic system in this brain region. There was no interaction between EPA, GLA, or AA and IL-1.
Following IL-1 injection, 5-HT and Trp levels were lower (P < 0.01 and P < 0.05, respectively), whereas 5-HIAA and 5-HIAA:5-HT levels were higher (P < 0.05 and P < 0.01, respectively) compared those in saline-treated rats. Only the EPA-enriched diet attenuated the change in the 5-HT turnover induced by IL-1 (P < 0.05).
Effects of diets on frontal cortical neurotransmitters and metabolites. Saline-treated rats Compared with the SAL-PALM group, there was a lower HVA concentration in the SAL-AA group and a higher Trp concentration in the SAL-EPA group (P < 0.05) (Table 4).
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IL-1 reduced DA but increased HVA concentrations (P < 0.05) without affecting the DOPAC:DA ratio (ratio not shown). EPA restored the DA concentration after IL-1 administration (P < 0.05) and reduced HVA concentrations (P < 0.05). Other diets did not have these effects (Table 4).
The 5-HIAA concentration tended to be higher (P = 0.06) in the IL1-PALM group than in the SAL-PALM group. EPA diet attenuated the change (P < 0.05) (Table 4). Other diets did not have an interaction with IL-1.
Effects of diets on hypothalamic neurotransmitters and metabolites. Saline-treated rats The effects of palm, EPA, and GLA diets on MHPG and NA concentrations (results not shown) and the MHPG:NE ratio did not differ, whereas AA increased the ratio (P < 0.05). Concentrations of DA, DOPAC, and HVA did not change in the SAL-EPA, SAL-GLA, or SAL-AA groups. There were no significant changes in 5-HT, its precursor, metabolites, and the ratio among saline treated groups fed the different diets (Table 5).
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In the IL1-PALM group, a higher DA concentration and lower DOPAC:DA ratio than these variables in the SAL-PALM group were observed (P < 0.05). None of the diets in this study attenuated IL-1–induced changes in the DA and its metabolites. The interaction between GLA and IL-1 induced a lower DOPAC level compared with the SAL-GLA group (P < 0.05) (Table 5).
IL-1 administration markedly decreased the concentration of 5-HIAA and Trp in rats fed the palm oil diet (P < 0.05) (Table 5). Only EPA reversed Trp reduction (P < 0.05) and no diet significantly modulated IL-1–induced change in 5-HIAA (Table 5).
PGE2 concentrations
In the saline-treated groups, PGE2 concentrations did not differ in the hippocampus, amygdala, and hypothalamus among the groups fed palm oil, EPA, and GLA. The SAL-AA rats had a higher concentration of PGE2 (P < 0.05) than the SAL-PALM group.
In the hippocampus, the PGE2 concentration was higher in the IL1-PALM group (P < 0.01) than in the SAL-PALM group. The diets enriched with EPA or GLA significantly attenuated PGE2 elevation induced by IL-1 (Fig. 3A), but the AA-enriched diet had no effect. Similar results were found in the amygdala; a lower PGE2 concentration was found in IL1-PALM group, which was significantly attenuated by the diet enriched with EPA (Fig. 3B). The PGE2 concentration tended to be lower in the IL1-GLA group (P = 0.07) but not in the IL1-AA group (Fig. 3B). In the hypothalamus, no significant change was observed among the groups (results not shown).
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Il-10 concentrations were lower in the hippocampus (Fig. 4A), amygdala (Fig. 4B), and hypothalamus (Fig. 4C) of IL1-PALM rats compared with saline-treated rats (P < 0.05). EPA attenuated the reduction of IL-10 induced by IL-1 in the amygdala (P < 0.05) (Fig. 4B) and the hypothalamus (Fig. 4C). However, EPA did not upregulate IL-10 production in the hippocampus (Fig. 4A). GLA and AA also did not affect IL-10 reduction induced by IL-1 (Fig. 4).
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Corticosterone concentrations did not differ among groups fed palm oil, EPA, and GLA following saline treatment. A slight elevation in the corticosterone concentration was found in SAL-AA (P < 0.05) (Fig. 5). A higher corticosterone concentration also occurred in the IL1-PALM, IL1-GLA, and IL1-AA groups (P < 0.001). Only the EPA diet attenuated the elevation (P < 0.05) (Fig. 5).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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The 0.5% EPA-supplemented diet significantly increased concentrations of hippocampal DA, DOPAC, HVA, and 5-HT and increased Trp in the frontal cortex compared with the SAL-PALM group. In clinical studies, EPA has been reported to effectively treat depression (43,44). Decreased (n-3) fatty acid intake or blood concentrations have been associated with the onset of depression and Parkinson's disease (45,46). Neurotransmitter dysfunctions contribute to the etiology of psychiatric and neurodegenerative diseases, such as 5-HT deficiencies in depression and DA deficiencies in Parkinson's disease. The results from our study may for the first time, to our knowledge, provide evidence for why EPA is beneficial in treating these diseases. Our study has also shown that AA induced some changes in monoamines and metabolites that are different from EPA or GLA, such as decreased Trp and elevated turnovers of NA, DA, and 5-HT in the amygdala. Previously, we reported that a diet enriched with AA increases glucocorticoid secretion and induces anxiety-like behavior in the elevated plus maze (21). Elevated DOPAC:DA in the amygdala has been associated with some stress responses (47) and anxiety-like behaviors (48,49). An activated serotonergic system and reduced Trp content in the amygdala have also been implicated in the modulation of fear conditioning and induction of anxiety (50,51). Thus, the present study showed the association between the neurotransmitter changes and anxiety-like behavior after AA feeding. In addition, AA-induced release of corticosterone may be related to its effect on MHPG:NE in the hypothalamus, because increased NA turnover in this brain region may result in the activation of the HPA axis and corticosterone secretion (52,53). Furthermore, increased hippocampal PGE2 synthesis in the AA group may also contribute to the corticosterone elevation, because corticosterone secretion may be via the activation of brain PGE2 (33).
Previous studies have reported that rats fed an (n-3)-deficient diet for 2 generations had a large DA reduction in the frontal cortex in postmortem brain tissues and also in dialysates (54,55). Here, we did not find that the (n-3) fatty acid-free diet or AA-enriched diet [as an (n-3) deficient diet] induced a similar change in the DA concentration in the frontal cortex compared with the EPA group. The differences between our results and the results of others may be due to the markedly different feeding durations.
IL1-PALM rats had decreased NA concentration and turnover in the hippocampus and amygdala. IL-1–induced changes were significantly attenuated by EPA and GLA but not by AA. We previously reported that central IL-1 administration significantly impaired rat spatial memory in the Morris water maze (23), which can be improved by EPA treatment (23). We postulated that EPA attenuated IL-1–induced NA reduction, because central functions of NA involve the regulation of alertness, maintenance attention, mood, learning, and memory. The reduction of the NA concentration in the limbic system has been associated with impairment in spatial learning and memory in depressed patients (56–58). However, in the present study, both EPA and GLA significantly attenuated NA changes in the hippocampus and amygdala, but only EPA significantly improved spatial memory. Thus, other mechanisms should be considered. First, different effects of EPA and GLA on frontal cortex DA concentration may play a role in spatial memory. Decreased DA and increased DA metabolites have previously been associated with a deficit in spatial memory (59–61). In this study, IL-1 decreased DA and increased HVA in the frontal cortex. EPA attenuated both changes. Second, corticosterone may play a role because GLA did not affect it. Overproduction of glucocorticoids induces hippocampal atrophy and suppresses long-term potentiation (62,63). In the present study, only EPA but not GLA significantly reversed elevated levels of corticosterone following IL-1 administration. Third, GLA did not significantly attenuate the reduction of IL-10 in the brain. PGE2 concentrations increased and IL-10 decreased in the brain regions following central IL-1 administration. IL-10 is an antiinflammatory cytokine (64). Kelly et al. (65) demonstrated that IL-10 could significantly block the inhibition of long-term potentiation in the hippocampus induced by IL-1. The present study has demonstrated that both EPA and GLA have significant antiinflammatory effects in the brain by reducing PGE2. However, only EPA reversed IL-10 reduction; 0.5% GLA did not significantly reverse IL-10 reduction. In a previous study, we reported 0.5% GLA significantly reversed an IL-1–induced decrease in IL-10 concentration in the blood (21). A higher dose of GLA may be needed to block the IL-1 effect on IL-10 in the brain.
The IL1-PALM group had higher NA and MHPG concentrations in the frontal cortex and higher NA utilization in the hypothalamus than those in the SAL-PALM group. Previous studies have demonstrated that similar monoamine changes in the frontal cortex and hypothalamus are related to stress, anxiety, inflammation, and HPA axis activation (66–68). The locus coeruleus that promotes the response of the HPA axis to stress partially depends on NA excitatory effects in the frontal cortex (69). These 2 brain regions are involved in the hypothalamic corticotrophin-release factor and the locus coeruleus-NA systems during stress (70). In addition, increased levels of the DA metabolite HVA and the 5-HT metabolite 5-HIAA following acute central or peripheral IL-1 administration have previously been described (20,29,71,72). These changes are also similar to the brain response to a stressor or corticotrophin-release factor administration (36). The EPA-enriched diet attenuated increased MHPG, HVA, and 5-HIAA induced by IL-1, which is correlated with decreased corticosterone concentrations and decreased anxiety-like behavior in rats fed EPA. However, GLA and AA were less effective in counteracting these changes in neurotransmitters and metabolites; therefore, they were also less effective in attenuating the anxiety and corticosterone secretion induced by IL-1.
There may also be some different mechanisms involved in the antiinflammatory effects of EPA and GLA. GLA is a precursor of dihomo--linolenic acid, which undergoes oxidative metabolism by cyclooxygenases and lipoxygenases to produce antiinflammatory eicosanoids (prostaglandins of series 1 and leukotrienes of series 3) (73). On the other hand, EPA suppresses the synthesis of leukotriene B4 and PGE2 through limiting AA availability, which then inhibits thromboxane A2 and eicosanoid synthesis (74). A negative correlation between peripheral EPA content and productions of IL-1 and TNF-
has been reported (11). However, the mechanism responsible for the suppression of proinflammatory cytokines by (n-3) fatty acids remains unknown. Recent evidence suggests that the antiinflammatory effect of (n-3) fatty acids may be via indirectly altering the expression of inflammatory genes through effects on transcription factor activation (75).
In this study, only 1 dose of each lipid was evaluated, because we previously found the same fatty acids at the same doses significantly modulated central IL-1–induced changes in stress-related behavior and blood PGE2 and IL-10 concentrations (21). Dose effects of these fatty acids should be investigated in the future. It should be also emphasized that some neurotransmitter changes cannot be directly related to behavioral and corticosterone concentration changes. To our knowledge, this is the first study to compare the effects of 3 fatty acids on behavioral, neurotransmitter, and brain immune factors in control rats and an IL-1–induced neuroinflammatory model. There is no sufficient publication to compare our results with except limited reports that discuss the putative roles of AA and EPA in cognition and neurodegenerative diseases (76–79).
Due to laboratory limitations, we could not measure (n-3) and (n-6) fatty acids in the brain after feeding. However, many studies have demonstrated that (n-3) and (n-6) diets do change brain lipid compositions, which has been firmly related to their effects on neurotransmissions (80–82).
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FOOTNOTES |
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2 Author disclosures: C. Song, M. Manku, and D. F. Horrobin, no conflicts of interest.
6 Abbreviations used: AA, arachidonic acid; DA, dopamine; DHA, cosahexaenoic acid; DOPAC, 3,4-dihydroxyphenylacetic acid; EPA, eicosapentaenoic acid; GLA, -linolenic acid; 5-HIAA, 5-hydroxyindoleacetic acid; HPA, hypothalamic-pituitary-adrenal; 5-HT, serotonin; HVA, homovanillic acid; i.c.v., intracerebroventricular; IL-1, interleukin-1β; IL1-AA, rats fed 4.0% palm oil and 1% AA and injected with IL-1; IL1-EPA, rats fed 4.5% palm oil and 0.5% EPA and injected with IL-1; IL1-GLA, rats fed 4.5% palm oil and 0.5% GLA, and injected with IL-1; IL1-PALM, rats fed 5% palm oil and injected with IL-1; MHPG, hydroxyphenethyleneglycol; NA, noradrenaline; PG, prostaglandin; SAL-AA, rats fed 4% palm oil and 1% AA and injected with saline; SAL-EPA, rats fed 4.5% palm oil and 0.5% EPA and injected with saline; SAL-GLA, rats fed 4.5% palm oil and 0.5% GLA and injected with saline; SAL-PALM, rats fed 5% palm oil and injected with saline; Trp, tryptophan.
Manuscript received 25 June 2007. Initial review completed 14 August 2007. Revision accepted 31 January 2008.
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