Keywords

Introduction

Neural membranes contain glycerophospholipids, which contain a saturated fatty acid at the sn-1 position of glycerol moiety, whereas the sn-2 position bears a polyunsaturated fatty acid (arachidonic acid, ARA, 20:4, n-6) or docosahexaenoic acid, DHA (22:6, n-3). ARA belongs to the omega-6 family whereas DHA falls under the omega-3 family of essential fatty acids, respectively. Vegetable and fish oils are the most common sources of omega-6 and omega-3 fatty acids, respectively. Fatty acids belonging to omega-6 and omega-3 family not only provide neural membranes with their physical characteristics, such as acyl chain order and fluidity, stability, phase behavior, elastic compressibility, ion permeability, fusion, rapid flip-flop and packing [1], but also function as signaling molecules by supplying lipid mediators, which are formed by the oxidation process. An appropriate ratio of ARA to DHA in the brain promotes development, ameliorates cognitive functions, and provides protection against neurological diseases by enhancing repairing processes [1]. In addition, ARA and DHA also stimulate gene expression, boost synaptogenesis, neurogenesis, and induce and prevent oxidative stress, a process that results from an unbalance between prooxidant and antioxidant systems in the brain. Neurological oxidative stress is either induced by the failure of cell antioxidant (buffering) mechanisms or overproduction of reactive oxygen species (ROS), which are oxygen-based radicals formed in most mammalian cells through the activities of enzymes involved in the mitochondrial electron transport chain, epoxygenase (EPOX), lipoxygenase (LOX) or cyclooxygenase (COX), NAD(P)H oxidases or uncoupled nitric oxide synthase (NOS), and peroxidases, among others [2, 3]. They are normal by-products of healthy cellular metabolic processes and are known to play physiologically useful roles in cell signaling; for example, as part of the immunity-oriented “oxidative burst” [4]. Low levels of oxidative stress are needed for cell functions. The role of oxygen in cell survival is linked to its high redox potential, which makes it an excellent oxidizing agent capable of accepting electrons easily from reduced substrates. High levels of oxidative stress are central disruptor of neural cell homeostasis. It is well known that brain represents only ∼2 % of the total body mass and yet accounts for more than 25 % glucose and 20 % of the total consumption of oxygen [5]. In addition to high oxygen utilization, two more reasons make the brain most susceptible to oxidative damage. First is its modest antioxidant defense mechanism and second is the presence of high levels of lipids, which account for 60–65 % of brain dry weight. Thus, the brain is particularly vulnerable to oxidative stress. The major sources of ROS in brain are uncontrolled ARA cascade, mitochondrial respiratory chain, xanthine/xanthine oxidase, myeloperoxidase, and activation of NADPH oxidase (Fig. 19.1).

Fig. 19.1
figure 1

Factors contributing to oxidative and antioxidant activities in the brain

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Long-term consumption of Western diet, which is enriched in saturated fats, ARA, cholesterol, and high simple sugars results in the incorporation of ARA in neural membrane phospholipids (phosphatidylinositol and phosphatidylcholine). ARA is released and oxidized by phospholipase A2 and cyclooxygenases-2 (PLA2 and COX-2) respectively [6]. Nonenzymic oxidation of arachidonic acid results in the generation of high levels of ROS, increased expression of inflammatory cytokines (TNF-α, IL1β, and IL-6), and elevated levels of n-6 fatty acid-derived proinflammatory lipid mediators (eicosanoids and platelet-activating factor) throughout the body including brain. Nonenzymic peroxidation of ARA is a radical-initiated and autocatalytic process. Free radicals are molecules that contain an unpaired electron in their outer orbit. Free radicals are associated with many neurochemical activities of cells such as signal transduction, gene transcription, and regulation of soluble guanylate cyclase activity. Humans are constantly exposed to free radicals not only generated from the man-made environment, but also from natural resources such as radon, cosmic radiation, as well as cellular metabolisms (respiratory burst, enzyme reactions). The most common reported cellular free radicals are hydroxyl (OH·), superoxide (O ·−2 ), and nitric monoxide (NO·) [1, 2]. ARA is highly susceptible to radical-mediated oxidation due to the abstraction of the bis-allylic methylene hydrogen by other radical species. The resulting conjugated pentadienyl fatty acid radical (L·) can further react with oxygen to give a dienyl peroxyl radical (LOO·). This intermediate abstracts a radical from another lipid generating a lipid hydroperoxide (LOOH) and a secondary radical. The lipid hydroperoxide (LOOH) undergoes rearrangement and cleavage reactions that result in the formation of lipoxidation end products. This process generates several products, such as 4-hydroxynonenal, malondialdehyde, acrolein, isoprostane, isofuran, and isoketal (Fig. 19.2) along with excessive production of ROS. High levels of ROS not only cause more lipid peroxidation and oxidation of neural membrane protein and DNA, but also produce impairment in normal neural cell functions leading to neural cell death [7]. Modifications of neural membrane protein and DNA were originally considered solely as markers of oxidative insult. However, recently the modifications of proteins and DNA by lipid peroxidation products are recognized as a new mechanism of cell signaling with relevance to redox homeostasis, adaptive response, and inflammatory resolution [8]. Among the neural cells, astrocytes are most resistant to ROS attack than neurons because they contain higher levels of reduced glutathione (GSH) content than other neural cells [9]. During scavenging of ROS, the reduced form of GSH is converted into oxidized form of glutathione (GSSG). Thus, high levels of ROS generation promote disruption of redox signaling in neural cells [9].

Fig. 19.2
figure 2

Chemical structures of arachidonic acid-derived lipid mediators in the brain

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The main impact of high levels of n-6 fatty acid consumption in Western diet is the generation of high levels of superoxide in the mitochondria [1]. Superoxide is a relatively unstable intermediate and in large part is converted to hydrogen peroxide in the mitochondria by superoxide dismutase. The newly formed hydrogen peroxide undergoes a Haber–Weiss or Fenton reaction, generating a highly reactive hydroxyl radical, which can oxidize mitochondrial proteins, DNA, and lipids and amplify the effects of the superoxide-initiated oxidative stress [10, 11]. Molecular mechanisms associated with nuclear and mitochondrial DNA (mtDNA) are not fully understood. However, it is suggested that promoter regions with high guanine–cytosine contents in DNA are specifically vulnerable to oxidative damage. Oxidative damage to promoter regions of DNA may cause changes in conformation leading to loss of DNA affinity for transcription factors [12]. Furthermore, oxidative damage to mitochondrial DNA (mtDNA) may result in downregulation of genes related to respiratory chain leading to impairment in energy metabolism [13, 14]. In addition, telomeres, regions of repetitive nucleotide sequences at each end of a chromosome, are highly susceptible to oxidative stress because of their high content of guanines. Increase in intracellular ROS levels is associated with acceleration in the rate of telomere shortening. Oxidative stress-mediated progressive shortening of telomeres leads to senescence, apoptotic cell death, or the oncogenic transformation of somatic cells in various tissues [15].

As stated above, ARA is released by the action of PLA2 on neural membrane phospholipids. It is oxidized by COXs and LOXs into proinflammatory eicosanoids (prostaglandins and leukotrienes) or nonenzymically oxidized into lipid mediators of arachidonic acid metabolism (Fig. 19.2) along with production of ROS. The generation of high ROS activates redox-sensitive transcription factor (NF-κB) that results in numerous downstream effects, including the increased expression of proinflammatory cytokines leading to further increase in ROS production (Fig. 19.3). Production of ROS is also promoted by RAGE receptors, which are activated by advanced glycation products (AGEs). AGEs are generated by an irreversible reaction through the nonenzymatic, long-term glycosylation of proteins. They are strongly resistant to proteolytic processes and induce protein cross-linking. They inhibit the physiological functions of many proteins and receptors promoting the transformation of soluble proteins into insoluble proteins deposits, as well as activating the microglia through specific ligands for cell surface receptors (Fig. 19.3). The complex interplay between inflammatory mediators and markers for oxidative stress caused by the long-term consumption of Western diet has been proposed to regulate the progression of chronic neurodegeneration in neurodegenerative diseases [15, 16]. In addition, nitric oxide (NO) synthesis occurs in mitochondria from the breakdown of arginine into citrulline by a family of NADPH-dependent enzymes called mitochondrial nitric oxide synthases (mtNOS) [17]. Once formed, NO inhibits respiration by binding to heme groups in the proteins of the electron transport chain, including cytochrome c oxidase [18, 19]. Thus, NO is a known inhibitor of the respiratory chain. NO competes directly with O2 at complex IV, reversibly retarding the formation of this complex and inducing ROS generation [20]. During high oxidative stress, NO reacts rapidly with excess superoxide to form peroxynitrite (Fig. 19.3), a powerful oxidizing and nitrating agent, which irreversibly inhibits multiple complexes of the respiratory chain, as well as dismutase enzymes. These processes not only lead to elevation in oxidative stress and increase in mitochondrial inner membrane potential (ΔΨ m) [21], but also induce alterations in calcium homeostasis [22]. Collective evidence suggests that oxidative stress and inflammation caused by distinct biochemical cascades are processes, which are closely intertwined and generally function in parallel, particularly in the brain, an organ especially prone to oxidative stress.

Fig. 19.3
figure 3

Signal transduction processes contributing to oxidative stress and neuroinflammation in the brain plasma membrane (PM), phosphatidylcholine (PtdCho), arachidonic acid (ARA), lysophosphatidylcholine (lyso-PtdCho), platelet-activating factor (PAF), glutamate (Glu), N-methyl-D-aspartate receptors (NMDA-R), cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), lipoxygenase (LOX), reactive oxygen species (ROS), advanced glycation end products (AGEs), receptors for advanced glycation end products (AGEs), nuclear factor-kappa B (NF-κB), nuclear factor-kappa B response element (NF-κB-RE), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), nitric oxide (NO), and peroxynitrite (ONOO−)

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Enzymic and Nonenzymic Lipid Mediators of ARA-Derived Metabolism and Their Antioxidant and Anti-inflammatory Effects

Stimulation of glutamatergic, serotonergic, cholinergic, or dopaminergic receptors by their agonists in the brain results in the activation of Ca2+-dependent PLA2 and release of arachidonic acid. The released ARA is oxidized by COXs, LOXs, and EPOXs resulting in the formation of prostaglandins (PGs), leukotriene (LTs), lipoxins (LXs), and thromboxanes (TXs), as well as hydroxyl-eicosatetraenoic acid, epoxyeicosatetraenoic acids, and dihydroxy-eicosatrienoic acids [23, 24]. Most arachidonic acid-derived lipid mediators produce prooxidant, prothrombotic, proaggregatory, and proinflammatory effects. However, arachidonic acid-derived LXs produce anti-inflammatory effects. PGs, LTs, and TXs interact with their receptors and produce potent effects on neuroinflammation, vasodilation, vasoconstriction, apoptosis, and immune responses [23, 24]. The expression of COX-2 is increased during acute inflammation and the ingestion of aspirin leads to acetylation of COX-2, which blocks PG formation [25]. Acetylated COX-2 is catalytically active. It transforms ARA into 15(R)-HETE rather than PGs [26]. 15(R)-HETE is utilized by 5-LOX for transforming into 15(R)-LXA4. Aspirin-triggered 15-epi-LXs are ∼twofold more potent than 15(S)-LXs [27].

ROS also attack on lipid hydroperoxides. This attack results in the synthesis of isoprostanes (IsoPs) via β-cleavage of the peroxyl acid and subsequent molecular rearrangement. IsoP contains D-, E-, and F-ringed structures similar to cyclooxygenase-generated prostaglandins, except that their hydrocarbon chains are in the cis position in relation to the pentane ring as opposed to the trans position observed in prostaglandins [24, 28, 29]. The formation of IsoP is used as a “gold standard” to quantify cumulative oxidative stress in neurological diseases. Neurochemical activities of IsoPs are poorly understood [24, 30–32]. However, they may form covalent adducts with cysteine residues in proteins through Michael-type addition reactions [33].

Enzymic and Nonenzymic Lipid Mediators of Omega-3 Fatty Acids

Phospholipids containing DHA account for as much as 15–25 mol% of the lipids of the gray matter in the human brain. It is estimated that 50 % of the weight of a neuronal plasma membrane is composed of DHA [34]. Among phospholipids, DHA is highly enriched in ethanolamine plasmalogen and phosphatidylserine in human brain. Small amount of eicosapentaenoic acid (EPA, 20:5 n-3), another omega-3 fatty acid, is also present in neural membrane phospholipids. From neural membrane phospholipids, DHA is released by the action of plasmalogen-selective and phosphatidylserine-selective PLA2s. In neural membranes, DHA and EPA play important roles in modulation of membrane fluidity and synaptic plasticity. DHA also protects neurons from cytotoxicity caused by high levels of nitric oxide (NO) and calcium (Ca2+) influx. In addition, DHA-deficient mice exhibit a range of neurocognitive impairments, including problems with learning and memory [35]. Furthermore, DHA has been reported to protect the neural cells from oxidative stress by increasing glutathione reductase activity and decreasing the accumulation of oxidized proteins [36, 37], lipid peroxide, and reactive oxygen species (ROS) [38]. In the murine microglial cell line BV2, DHA reduces proinflammatory molecule synthesis, migration, and lipid droplet formation and induces heme oxygenase-1 expression, by mechanisms involving alteration of lipid raft composition and modulation of PtdIns 3-kinase/Akt, ERK, and NF-κB-mediated signaling [39, 40]. DHA is also known to retard caspase cascade [36] through the regulation of the PtdIns 3K/Akt cascade [41]. Omega-3 fatty acids are not only natural ligands of nuclear receptors associated with the regulation of gene expression (PPAR, hepatic nuclear factor, liver X receptors, and retinoid X receptors), but also involved in modulation of transcription factors, such as sterol regulatory element-binding protein and carbohydrate response element-binding protein [42]. Furthermore, omega-3 fatty acids also modulate genes involved in insulin sensitivity (PPARγ), glucose transport (GLUT-2/GLUT-4), and insulin receptor signaling (IRS-1/IRS-2). In addition, omega-3 fatty acids also increase adiponectin, an anti-inflammatory and insulin-sensitizing adipokine, and induce AMPK phosphorylation, a fuel-sensing enzyme and a gatekeeper of the energy balance [15]. All these mechanisms are interconnected and closely associated with modulation of carbohydrate and lipid metabolism involved in modulation of oxidative stress and inflammation in the brain. Collective evidence suggests that in the brain, DHA is involved in development, neurogenesis, memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling [43].

Enzymic and Nonenzymic Lipid Mediators of EPA Metabolism and Their Antioxidant and Anti-inflammatory Effects

Like ARA, EPA also undergoes enzymic and nonenzymic oxidation leading to the production of a variety of lipid mediators [24]. The enzymic oxidation of EPA results in the formation of E-series resolvins (RvE1 and RvE2), 3-series PGs, and 5-series LTs [44]. These metabolites produce potent anti-inflammation/pro-resolution effects in vivo [45]. They bind to ChemR23 and BLT receptors (seven-membrane spanning G protein-coupled receptors), which are expressed and located on dendritic cells and monocytes [46]. RvE1 has been reported to suppress the activation of NF-κB and tumor necrosis factor-alpha (TNF-α) by interacting with human polymorphonuclear leukocyte (PMN) [47]. RvE1 also produces anti-inflammatory effects by decreasing neutrophil infiltration, paw edema, and proinflammatory cytokine expression [48]. EPA is also oxidized by COX and LOX enzymes. This oxidation results in the generation of 3 series of prostaglandins and thromboxanes and 5 series of leukotrienes (Fig. 19.4). These eicosanoids have different biological properties than the corresponding analogs generated by the oxidation of ARA. Thus, TXA3 is less active than TXA2 in aggregating platelets and constricting blood vessels [44].

Fig. 19.4
figure 4

Generation of ARA-, EPA-, and DHA-derived lipid mediators and their neurochemical effects on arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5_LOX), and 15-lipoxygenase (15-LOX); ARA-derived eicosanoids are PGE2, PGI2, LTB4, LTC4, and TX2; EPA-derived eicosanoids are PGI3, PGE3, LTB5, LTC5, LTE5, and TXA3; and DHA-derived metabolites are D-series resolvins (D-series Rvs) and neuroprotectin D1 (NPD1). In the presence of aspirin, a new set of lipid mediators called aspirin-triggered resolvins and protectins are synthesized

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Antioxidant effects of EPA involve nonenzymic oxidation of EPA. The nonenzymic oxidation of EPA results in the synthesis of cyclopentenone-isoprostanes (A3/J3-IsoPs) [49]. These metabolites modulate the Keap1-Nrf2-ARE pathway (Fig. 19.4). Nrf2 transcription factor is a member of the leucine zipper transcription factor family [50, 51]. It is present in the cytoplasm as a complex with Kelch-like ECH-associated protein 1 (Keap1). Interactions of A3/J3-IsoP with Keap1 not only results in the dissociation of Nrf2 from Keap1, but also in translocation of Nrf2 into the nucleus. In the nucleus, Nrf2 heterodimerizes with the small Maf proteins and binds to specific response elements termed antioxidant or electrophilic response elements (AREs) to coordinate expression of cytoprotective genes, such as genes associated with antioxidant-detoxifying proteins, genes involved in cellular rescue pathways against oxidative injury, inflammation/immunity, and apoptosis. ARE-modulated genes include glutathione peroxidases, glutathione S-transferase, heme oxygenase, NAD(P)H: quinone oxidoreductase 1 (NQO1), and proteasome subunit beta type-5 [52, 53]. Collective evidence suggests that the major function of Nrf2 is to activate the cellular antioxidant response by inducing the transcription of a wide array of genes that are able to combat the harmful effects of oxidative stress. Because of this reason, Nrf2 is traditionally been regarded as the cell’s major antioxidant mechanism and Nrf2 is a major regulator of cell survival [53].

Enzymic, Nonenzymic Lipid Mediators of DHA Metabolism and Their Antioxidant and Anti-inflammatory Effects

The enzymically derived lipid mediators of DHA metabolism include D-series resolvins, neuroprotectins (NDPs), and maresins (MaR) (Figs. 19.4 and 19.5). These lipid mediators are collectively known as docosanoids [24]. They not only downregulate proinflammatory cytokines but also produce antioxidant, anti-inflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory effects [1, 43, 54–57]. Resolvin Ds are synthesized from DHA through the action of 15-lipoxygenase (15-LOX). This reaction results in the formation of 17S-hydroperoxy-DHA [55, 58, 59]. Enzymic peroxidation and hydrolysis transform 17S-hydroperoxy-DHA into neuroprotectin D1 (NPD1). D-series resolvins (Rvs) and their aspirin-triggered epimers are also synthesized from DHA through a pathway with sequential oxygenations, initiated by 15-LOX or aspirin-acetylated COX-2, respectively [27, 54]. Finally, MaRs are synthesized by 14-lipoxygenation of DHA. This process produces 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S-HpDHA), which undergoes further conversion via 13(14)-epoxidation, leading to the synthesis of 7,14-dihydroxydocosa-4Z,8Z,10,12,16Z,19Z-hexaenoic acid (MaR1) [60]. These DHA-derived metabolites provide powerful anti-inflammatory and immunomodulatory roles by reducing the migration of neutrophils and the release of pro-inflammatory cytokines [55, 57]. These metabolites also protect against oxidative damage that is associated with a localized inflammatory response by blocking the migration of PMN to injured tissues, thereby retarding the oxidative stress that stems from PMN activation [55, 57]. In microglia cells, resolvins block the production of pro-inflammatory cytokines such as TNF-α and ILβ1. DHA also reduces pro-inflammatory mediators such as prostaglandin E2, thromboxanes, and leukotrienes [61]. In brain and retina, the generation of NPD1 results in the expression of antiapoptotic protein and downregulation of caspase-3 activation and decrease oxidative stress [62]. NPD1 also promotes Akt translocation and activation and interacts with PPAR-gamma family of ligand-activated nuclear receptors, which may be involved in various aspects of oxidative stress and neuroinflammation [24, 63, 64]. The occurrence of NPD1 receptors in brain has not been reported, but based on pharmacological studies, it is suggested that NPD1 receptors may occur in neural tissues [43, 54, 62]. Collective evidence suggests that NPD1 not only retards apoptosis and modulates neuroinflammatory signaling, but also promotes the cellular homeostasis, and restoration of brain damage through its antioxidant, anti-inflammatory, and antiapoptotic effects. This is tempting to speculate that the generation of DHA-derived resolvins and NPD1 and synthesis of ARA-derived lipoxins may be internal neuroprotective mechanisms that may protect from brain damage caused by neurotraumatic and neurodegenerative diseases [24, 58, 59].

Fig. 19.5
figure 5

Chemical structures of DHA-derived lipid mediators

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The nonenzymic lipid mediators of DHA metabolism include 4-hydroxyhexanal (4-HHE), neuroprostanes (NPs), neuroketals (NKs), and neurofurans (NFs) (Fig. 19.6). Among these lipid mediators, NKs and NFs promote prooxidant and proinflammatory effects, but NPs possess anti-inflammatory properties and also inhibit proteasome activity [65, 66]. ARA- and DHA-derived nonenzymic lipid mediators act synergistically to modulate induction and regulation of neuroinflammation and oxidative stress by controlling the duration and magnitude as well as the return of the injury site to homeostasis in the process of catabasis (the decline of the disease state) [55]. An important function of ARA-, EPA-, and DHA-derived lipid mediators is their involvement in signal transduction network, which conveys the message of extracellular signals from the cell surface to the nucleus to induce a biological response at the gene level. Levels of ARA, EPA, and DHA in diet may partially modulate the levels of their lipid mediators in neural and non-neural tissues. Thus, levels of ARA, EPA, and DHA and their lipid mediators not only modulate the onset of neuroinflammation and oxidative stress by coupling lipid metabolism with neural membrane lipid organization, but also cooperate with the action of lipid-dependent enzymes to execute appropriate downstream actions and responses [24].

Fig. 19.6
figure 6

Chemical structures of DHA-derived nonenzymic lipid mediators

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Prevention of Oxidative Stress and Neuroinflammation by EPA and DHA

It is well known that in Western diet, the ratio between ARA and DHA is about 20:1 [1]. In contrast, Paleolithic diet on which humans have lived and survived thousands of years contained the ratio between ARA and DHA of 1:1 [67, 68]. Due to the presence of high levels of ARA, long-term consumption of Western diet results in the generation of high levels of ARA-derived enzymic (PGs, LTs, and TXs) and nonenzymic (4-HNE, IsoP, MDA, etc.) lipid mediators, which promote neuroinflammation and oxidative stress, along with apoptotic cell death [1, 15, 69]. As stated above, oxidative stress and neuroinflammation are closely intertwined processes that generally function in parallel, particularly in the brain, an organ especially prone to both oxidative stress and neuroinflammation. These processes are also closely associated with the pathogenesis of neurotraumatic, neurodegenerative, and neuropsychiatric diseases [16]. In addition, consumption of Western diet induces obesity, which correlates with reduction in focal gray matter volume and enlargement in white matter in the frontal lobe [70], altering learning, memory, and executive function in humans [71] and cognitive deficits in a rodent model [72]. Furthermore, long-term consumption of Western diet also decreases levels of BDNF in the hippocampus leading to impairment in neurogenesis [69]. Consumption of the Western diet also mediates significant decrease in Nrf2 DNA-binding activity, reduces Nrf2 responsive pathway proteins (heme oxygenase-1 and NAD(P)H dehydrogenase, quinone 1), and decreases the expression of Nrf2 protein expression [73, 74] as depressive symptoms. Collective evidence suggests that long-term consumption of Western diet increases the chances of brain damage through oxidative processes along with changes in neural cell homeostasis leading to metabolic abnormalities, behavioral disturbances, and motor and cognitive impairments. Increase in fish consumption or inclusion of fish oil in the diet not only decreases levels of ARA-derived enzymic and nonenzymic lipid mediators, but also generates DHA- and EPA-derived lipid mediators (D-series Rvs, E-series Rvs, NPD1, and MaRs) [24]. These omega-3 fatty acid-derived lipid mediators produce antioxidant and anti-inflammatory effects and retard the onset and pathogenesis of neurotraumatic, neurodegenerative, and neuropsychiatric diseases [1, 16]. It is also proposed that consumption of omega-3 fatty acid-containing diet counteracts signals that respond to oxidative stress and set in motion brain repair and neuroplasticity responses needed for achieving neural cell homeostasis [1].

Conclusion

Consumption of high levels of ARA produces high levels of ARA-derived enzymic and nonenzymic lipid mediators along with generation of ROS, which react with DNA, proteins, and lipids and play important roles in the pathogenesis of neurotraumatic, neurodegenerative, and neuropsychiatric disease. Consumption of DHA- and EPA-containing food (fishes or fish oil) results in the production of resolvins and protectins/neuroprotectins. These lipid mediators regulate immune systems by modulating signal transduction processes associated with oxidative stress, neuroinflammation, and neurodegeneration. EPA-derived resolvins (i.e., RvE1 and RvE2) and DHA-derived resolvins (RvD1 and RvD2) produce potent antioxidants, anti-inflammatory, and pro-resolution effects. They inhibit oxidative stress, retard excessive inflammation, and promote resolution by enhancing clearance of apoptotic cells and debris from inflamed brain tissue. These properties result in the beneficial effects of EPA and DHA in human health and neurotraumatic and neurodegenerative diseases.