Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

Js, Rao; Hj, Lee; Si, Rapoport; Rp, Bazinet

doi:10.1038/mp.2008.31

Cited by 109 publications

(94 citation statements)

References 177 publications

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“…These effects are approximately opposite of what was observed with the low versus high n-3 PUFA diets in previous studies where low n-3 PUFA leads to conservation of DHA but not ARA ( 10,11 ). Recently, the Nurses' Health Study reported that an elevated intake of LA was associated with an increased risk of developing major depression ( 50 ), and preclinical studies suggest that drugs used to manage bipolar disorder decrease brain arachidonic acid metabolism ( 51,52 ). While much interest in dietary LA levels have focused around coronary heart disease risk, understanding how dietary n-6 PUFAs regulate the metabolism of ARA and DHA in the brain may also be important for determining dietary requirements.…”

Section: Resultscontrasting

confidence: 38%

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids

Lin

Chen

Hildebrand

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org disease, Parkinson's disease, bipolar disorder, and major depression ( 7-9 ).ARA and DHA can either be obtained directly from the diet or synthesized from their nutritionally essential precursor fatty acids linoleic acid (18:2n-6; LA) and ␣ -linolenic acid (18:3n-3; ALA) respectively, which are the main dietary n-6 and n-3 PUFAs. Thus, it is of interest to determine whether changes in the level of dietary n-6 or n-3 PUFAs can alter the concentrations of ARA and/or DHA in the brain, and more importantly, whether these dietary changes affect their metabolism. In fact, clinical trials in humans are underway, with the assumption that lowering n-6 PUFAs may decrease brain ARA and its metabolism ( 1 ).Several studies have investigated the effects of dietary n-3 PUFA deprivation on brain ARA and DHA concentrations and metabolism in rats. Feeding rats an n-3 PUFAdeprived diet that contains ALA at a concentration of 0.04% versus an n-3 PUFA-adequate diet containing ALA at 4.4% of all fatty acids decreased the concentration of DHA by 37% and increased docosapentaenoic acid (DPA) n-6 concentration by 95% in brain total phospholipids, but did not change the concentration of ARA ( 10 ). This study also reported that n-3 PUFA deprivation conserves DHA in rat brain phospholipids extending the half-life from 33 to 90 days. This conservation response was selective for DHA, as n-3 PUFA deprivation did not alter the half-life or rate of ARA metabolic consumption ( 11 ). Alterations in brain DHA concentration and metabolism appear to occur below a threshold of 0.8% ALA in the diet, Abstract To determine how the level of dietary n-6 PUFA affects the rate of loss of arachidonic acid (ARA) and DHA in brain phospholipids, male rats were fed either a deprived or adequate n-6 PUFA diet for 15 weeks postweaning, and then subjected to an intracerebroventricular infusion of 3 H-ARA or 3 H-DHA. Brains were collected at fi xed times over 128 days to determine half-lives and the rates of loss from brain phospholipids ( J out ). Compared with the adequate n-6 PUFA rats, the deprived n-6-PUFA rats had a 15% lower concentration of ARA and an 18% higher concentration of DHA in their brain total phospholipids. Loss half-lives of ARA in brain total phospholipids and fractions (except phosphatidylserine) were longer in the deprived n-6 PUFA rats, whereas the J out was decreased. In the deprived versus adequate n-6 PUFA rats, the J out of DHA was higher. In conclusion, chronic n-6 PUFA deprivation decreases the rate of loss of ARA and increases the rate of loss of DHA in brain phospholipids. Thus, a low n-6 PUFA diet can be used to target brain ARA and DHA metabolism. The brain is specifi cally enriched with the two PUFAs arachidonic acid (20:4n-6; ARA) and DHA (22:6n-3), which are considered important for normal brain function. Bioactive mediators from ARA and DHA, the eicosanoids and docosanoids, respectively, regulate many processes including neuroinfl ammation, pain perception, and blood fl ow...

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Section: Resultscontrasting

confidence: 38%

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids

Lin

Chen

Hildebrand

et al. 2015

Journal of Lipid Research

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“…[14][15][16][17][18][19] Moreover, a large body of data implies that inhibition of inflammation may contribute to the therapeutic effects of psychotropic drugs. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] However, it is important to emphasize that many studies reported opposite findings; namely, that psychotropic drugs also exhibit pro-inflammatory effects. 10,31,[38][39][40][41] Furthermore, the mechanism underlying the anti-inflammatory properties of psychotropic drugs is not fully understood and it is not known whether their influence on inflammation contributes to their therapeutic and toxic effects.…”

Section: Introductionmentioning

confidence: 99%

“…[56][57][58][59] Another inflammatory pathway that is frequently linked to the pathophysiology of neurological disorders is the cyclo-oxygenase (COX)-PGs cascade. 20,21 PGs such as PGE 2 not only have many important physiological functions, but also contribute to a number of pathological processes. [60][61][62][63] The biosynthesis of PGs involves the release of arachidonic acid (AA) from membrane phospholipids by phospholipase A 2 and its conversion to PGs by COX.…”

Section: Introductionmentioning

confidence: 99%

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

Faour-Nmarne

Azab

2015

Innate Immun

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Olanzapine (OLZ) is an atypical antipsychotic drug that also has mood-stabilizing effects. The mechanism of action of OLZ is not fully understood. Accumulating data suggest that inflammation plays a role in the pathophysiology of mental disorders and that psychotropic drugs exhibit some anti-inflammatory properties. This study was undertaken to examine the effects of OLZ on LPS-induced inflammation in rat primary glia cells. Glia cells were extracted from newborn rat brains. OLZ (1 or 50 mM) was added to culture medium at 6 or 72 h before addition of LPS for another 18 h, and levels of IL-10, prostaglandin (PG) E 2 , NO and TNF-a, and expression of cyclo-oxygensase (COX)-2 and inducible NO synthase (iNOS) were determined. Treatment with 50 mM OLZ (but not 1 mM) significantly decreased LPS-induced secretion of IL-10, PGE 2 and TNF-a. In contrast, 50 mM OLZ significantly increased NO levels. OLZ did not alter the expression of COX-2 or iNOS in LPS-treated cells. These results suggest that OLZ differently affects the secretion of inflammatory mediators. Most of the significant effects of OLZ were obtained when 50 mM was used, which is a high and probably therapeutically irrelevant concentration. Therefore, under the conditions used in the present study OLZ seemed to lack a potent anti-inflammatory effect.

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“…such as bipolar disorder, in which evidence points to a pathological upregulation of brain AA signaling ( 14 ).…”

mentioning

confidence: 99%

Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet

Green

Liu

Bazinet

2010

Journal of Lipid Research

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Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

Cited by 109 publications

References 177 publications

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids

Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids

Effects of olanzapine on LPS-induced inflammation in rat primary glia cells

Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet

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