Polyunsaturated fatty acids PUFAs represent a class of lipid

Polyunsaturated fatty acids (PUFAs) represent a class of lipids that contain two or more carbon double (unsaturated) bonds (CC) and classified as n-3, n-6 and n-9 fatty acids. PUFAs including n-3 such as docosahexaenoic flap inhibitor (DHA), eicosapentaenoic acid (EPA) and n-6 such as arachidonic acid (AA) are of great importance in the neurobiology as they are essential for the neurogesis, memory, learning, and emotions, development and maintenance of brain structure during embryonic and adult stage. Despite the fact that PUFAs are vital for normal biological processes, mammals are unable to achieve de novo synthesis of these fatty acids. Humans obtain PUFAs from different dietary sources. The richest source of DHA are fish and seafood while it can also be obtained from its precursor alpha-linolenic acid (ALA), enriched in the soybean, flax, chia, walnut and canola oils (Innis, 2003, Whelan and Rust, 2006, Rapoport et al., 2001). The synthesis process of DHA from ALA is only carried out by astroglia and endothelial cells of the blood vessels (Moore et al., 1991) and then transferred it to the neurons (Moore, 1993). However, in the human brain the chief source of PUFAs is dietary. In the neuronal membranes PUFAs are essential for the modulation of ion channels and neurotransmitter receptors. In fact an adequate lipid environment is vital for the normal functioning of neuronal membrane proteins such as ion channels, enzymes, ion pumps and receptors. Besides this, free fatty acids also act as a signaling molecule for regulation of gene expression (Duplus and Forest, 2002). PUFAs also play a significant role in the regulation of the endocannabinoid (eCB) system, which is a major regulator of mood and emotions (Hill and Gorzalka, 2009, Lutz, 2009). Anandamide, arachidonoylethanolamide and 2-arachidonoylglycerol are the principal signaling lipids of the eCB system. They are known to bind to G protein-coupled receptors CB1 and CB2 leading to activation of the mitogen activated protein kinase (MAPK) cascade (Bouaboula et al., 1995, Wartmann et al., 1995). The deregulation of the eCB system contributes to the development of depressive and anxiety-like symptoms. The eCB system is therefore in a unique position to link dietary lipids, synaptic activity, and emotional behavior. Research studies have shown that that long-term nutritional n-3 PUFA deficiency alters the eCB system and impairs synaptic plasticity in the brain. Radical alteration of endocannabinoid (eCB)-dependent synaptic plasticity was observed in the prefrontal cortex (PFC) of mice fed with an n-3 PUFA deficient diet throughout their life. Long-term exposure to an n-3 polyunsaturated fatty acids (PUFAs) deficient diet decreases the level of DHA in the brain and impairs the cannabinoid receptor signaling pathway in mood-controlling structures. Furthermore, decrease of DHA contents in the PFC was linked to reduced function of the synaptic cannabinoid receptor 1 (CB1) (Lafourcade et al., 2011a, Lafourcade et al., 2011b, Larrieu et al., 2012). Puente N et al, examined the interaction between 2-AG, anandamide and their cognate receptors by application of electrophysiological and electron microscopy. They observed that 2-arachidonoylglycerol (2-AG) and anandamide mediated different forms of plasticity in the extended amygdala of rats. Dendritic Ltype Ca2+ channels and the subsequent release of 2-AG acting on presynaptic CB1 receptors triggered retrograde short-term depression. Long-term depression was mediated by postsynaptic mGluR5-dependent release of anandamide acting on postsynaptic TRPV1 receptors (Puente et al., 2011). N-3 PUFA incorporation into the neuronal membrane also increases synaptic protein expression, strengthening the hippocampal synaptic plasticity (Su, 2010). This is modulated by transcription factors such as peroxisome proliferator activated receptors (PPARs) (Moreno et al., 2004). The PPAR family is composed of three different isotypes. They are known as PPARα (NR1C1), PPARβ (NR1C2) also named PPARδ, and PPARγ (NR1C3) (Dreyer et al., 1992; Issemann and Green, 1990) and each have distinct expression patterns, tissue distribution and physiological functions (Heneka and Landreth, 2007, Moreno et al., 2004). The activity of PPAR is relatively high in the brain (Ciana et al., 2007, Kao et al., 2012) and all of their isotypes are expressed in neurons, astrocytes, oligodendrocytes, and microglia (Heneka and Landreth, 2007). Endogenous ligands of PPARs include endocannabinoids, fatty acids and fatty acid derivatives (e.g., polyunsaturated fatty acids, eicosanoids and oxidized phospholipids) (Krey et al., 1997, Sun and Bennett, 2007). PPARγ has a prominent role in the regulation of central nervous system inflammation and neuroprotection (Pathan et al., 2008, Deplanque, 2004) leading to improvement in cognitive performance (Rinwa et al., 2010, Pathan et al., 2008). The PPARα plays an significant role in the regulation of acetylcholine biosynthesis that contributes to cognitive function (Moreno et al., 2004, Farioli-Vecchioli et al., 2001). These findings suggest that PUFAs play significant role in the enhancement of cognitive performance through PPAR nuclear receptors. PPAR agonists are the focus of intense interest for the treatment of CNS diseases including Alzheimer's, Huntington's disease and Parkinson's, schizophrenia, ischemic brain injury, obesity and metabolic disorders. The G protein-coupled receptor (GPCR) also known as the seven-transmembrane domain receptor (7TM) superfamily that mediates cellular responses to various physiological ligands such as photons, odors, pheromones, hormones, ions, steroids and small molecules including amines, amino acids to large peptides, and are therefore attractive targets for drug discovery (Shoichet and Kobilka, 2012). The tissue expression of all GPCR receptors are different, GPR43 is present in a large variety of tissues, including adipose tissue, inflammatory cells, and gastrointestinal (GI) tract (Le Poul et al., 2003), GPR120 is mainly expressed in human taste buds (Galindo et al., 2012) in both osteoclasts and osteoblasts, (Cornish et al., 2008), GPR84 is highly expressed in human bone marrow, and to a lesser extent, in the peripheral leukocytes and lungs (Wang et al., 2006a, Wang et al., 2006b, Lattin et al., 2008), GPR40 is highly expressed in pancreatic beta cells (Briscoe et al., 2003). Recently GPR40 expression was also confirmed in the (CNS) of primates (Ma et al., 2007). In the past half decade, deorphanization of numerous GPCRs has revealed that GPR40, GPR41, GPR43, GPR84 and GPR120 sense concentration of extracellular free fatty acids with various carbon chain lengths. Both GPR41 and GPR43 are activated by short chain fatty acids such as formate, acetate, propionate, butyrate and pentanoate (Brown et al., 2003, Nilsson et al., 2003). GPR84 is activated by medium-chain, but not long-chain FFAs. GPR120 is activated by medium- and long-chain FFAs (Yonezawa et al., 2013). GPR40 is activated by medium to long chain saturated and unsaturated fatty acids including PUFAs (Briscoe et al., 2003). Briscoe et al, have identified and determined the PUFAs agonist potencies at GPR40 receptor using increases in Ca2+ measured using FLIPR in HEK293 cells expressing GPR40 (Briscoe et al., 2003) (See Table 1).