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: ''For introductory details to this topic, including terminology and ω-3 / ω-6 nomenclature, see the main articles at Essential Fatty Acid and Eicosanoid .'' s and Animal Fat s. In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. found in, e.g. Borage Oil . These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less inflammatory essential fatty acids, especially the ω-3s, is associated with a variety of inflammation-related diseases. The Usual Diet In Industrial Countries contains much less ω-3 fatty acids than the diet even a century ago, and that diet had much less ω-3 than the diet of early Hunter-gatherer s. This has been accompanied by increased rates of many diseases – the so-called Diseases Of Civilization – that involve inflammatory processes. There is now very strong evidence (National Institute of Health, 2005) that several of these diseases are ameliorated by increasing dietary ω-3, and good evidence for many others. There is also more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders. EICOSANOID SERIES NOMENCLATURE : ''For details on the metabolic pathways for Eicosanoid s in each series, see the main articles for Prostaglandin s (PG), Thromboxane s (TX), Prostacyclin s (PGI) and Leukotriene s (LK). Eicosanoids are signalling molecules derived from the EFAs; they are a major pathway by which the EFAs act in the body. There are four classes of eicosanoid and two or three series within each class. Before discussing eicosanoid action, we will explain the series nomenclature. Cell's outer Membranes contain Phospholipid Fat . Each phospholipid molecule contains two Fatty Acid s. Some of these fatty acids are 20-carbon Polyunsaturated essential fatty acids – AA, EPA or DGLA. In response to a variety of inflammatory signals, these EFAs are cleaved out of the phospholipid and released as free fatty acids. Next, the EFA is oxygenated (by either of two pathways), then further modified, yeilding the eicosanoids. (Dorlands, entry at "Prostaglandins") Cyclooxygenase (COX) oxidation removes two C=C Double Bonds , leading to the TX , PG and PGI series. Lipoxygenase oxidation removes no C=C double bonds, and leads to the LK . (Cyberlipid Center.) After oxidation, the eicosanoids are further modified, making a ''series''. Members of a series are differentiated by an ''ABC...'' letter, and are numbered by the number of double bonds, which does not change within a series. For example, cyclooxygenase acts upon AA (with 4 double bonds) to generate the series-2 thromboxanes (TXA2, TXB2... ) each with two double bonds. All the prostenoids are substituted prostanoic acids. Cyberlipid Center's Prostenoid page illustrates the parent compound and the rings associated with each series–letter. Figure (1) shows these sequences for AA (20:4 ω-6). The sequences for (20:3 ω-6) are analogous.
ARACHIDONIC ACID CASCADE IN INFLAMMATION In the arachidonic acid cascade, dietary into the Phospholipid fats in the Cell Membrane . Next, in response to many inflammatory Stimuli , Phospholipase is generated and cleaves this fat, releasing AA as a Free Fatty Acid . AA can then be oxygenated and then further modified to form Eicosanoid s – Autocrine and Paracrine Agents that bind Receptors on the cell or its neighbors. Alternatively, AA can diffuse into the Cell Nucleus and interact with Transcription Factor s to control DNA Transcription for Cytokine s or other hormones. Mechanisms of ω-3 eicosanoid action The eicosanoids from AA generally promote inflammation. Those from GLA (''via'' DGLA) and from EPA are generally less inflammatory, or inactive, or even anti-inflammatory. (This generalization is qualified: an eicosanoid may be pro-inflammatory in one tissue and anti-inflammatory in another. ''See'' discussion of PGE2 at (Calder, 2004)) Figure (2) shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways – displacement, Competitive Inhibition and direct counteraction. Displacement Dietary ω-3 decreases tissue concentrations of AA. Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue. (Medical News Study, 2005) enzymes that produce AA. EPA inhibits Phospholipase A2's release of AA from cell membrane. (Su ''et al'' 2003) Other mechinisms involving the transport of EFAs may also play a role. The reverse is also true – high dietary lineolate decreases the body's conversion of α-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for α-linolenic acid than it does linoleic acid. (Phinney, 1990) Competitive Inhibition DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosonoids. For example, dietary GLA increases tissue DGLA and lowers TXB2. (Guivernau, 1994) (Karlstaad, 1993) Likewise, EPA inhibits the production of series-2 PG and TX. (Calder, 2004) Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs. (Belch 2000) Counteraction Some DGLA and EPA derived eicosonoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2. (Fan, 1998) EPA yields the antiaggregatory prostacyclin PGI3 (Fischer, 1985) It also yields the leuokotriene LKB5 which vitiates the action of the AA-derived LKB4. (Prescott, 1984) The paradox of dietary GLA Dietary Linoleic Acid (LA, 18:2 ω-6) is inflammatory. In the body, LA is desaturated to form GLA (18:3 ω-6). But dietary GLA is anti-inflammatory. How is this possible? Some observations paritally explain this paradox. LA competes with . Δ6-desaturase does appear to be the rate-limiting step; 20:4 ω-3 does not significantly accumulate in bodily lipids. DGLA inhibits inflammation through both competitive inhibition and direct counteraction (see Above .) Dietary GLA leads to sharply increased DGLA in the white blood cells' membranes, where LA does not. This may reflect white blood cells' lack of desaturase. (Fan, Chapkin 1998) It is likely that some dietary GLA eventually forms AA and contributes to inflammation. Animal studies indicate the effect is small, (Karlstad ''et al'', 1993) The empirical obseration of GLA's actual effects argues that DGLA's anti-inflammatory effects dominate. (Stone ''et al'', 1979) THE ARACHIDONIC ACID CASCADE IN THE CNS
"The arachidonic acid cascade is arguably the most elaborate signaling system neurobiologists have to deal with." – Piomelli, 2000 The arachidonic acid cascade proceeds somewhat differently in the brain. Neurohormone s, Neuromodulator s or Neurotransmitter s act as first messengers. They activate phospholipidase to release AA from Neuron cell membranes as a free fatty acid. During its short lifespan, free AA may affect the activity of the neuron's Ion Channel s and Protein Kinase s. Or it may be metabolized to form eicosanoids, Epoxyeicosatrienoic Acid s (EETs), Neuroprotectin D or various Endocannabinoids ( Anandamide and its analogs.) The actions of eicosanoids within the brain are not as well characterized as they are in inflammation. It is theorized that they act within the neuron as Second Messenger s controlling presynaptic inhibition and the activation of Protein Kinase C . They also act as paracrine mediators, acting across synapses to nearby cells. Although detail on the effects of these signals is scant, (Piomelli, 2000) comments
The EPA and DGLA cascades are also present in the brain and their eicosanoid metabolites have been detected. The ways in which these differently affect mental and neural processes are not nearly as well characterized as are the effects in inflammation. SOURCES
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