DHA represents more than 90% of the n-3 LCPUFA in the brain [31], mainly as part of the membrane phospholipids in the brain gray matter [6,96], constituting 35% of the total fatty acids in the synaptic membranes [97]. DHA is primarily esterified to phosphatidylethanolamine, phosphatidylserine, and to a lesser extent phosphatidylcholine in neuronal membranes. The structural properties of DHA, such as the length of its carbon chain and its six double bonds, give flexibility and fluidity to the neuronal plasma membrane, facilitating signal transduction into the cell [10,11]. The fluidity of the neuronal membrane facilitates the lateral movement of receptors, G proteins, ion channels [98], enzymes [99], and neuroreceptors, increasing the efficiency in signal transduction [100,101,102]. In the brain, DHA is involved in neuronal growth, neuronal migration, synaptogenesis, synaptic plasticity, and gene expression [11,12,13,103]. Neurons cannot form DHA from its precursor ALA, but the glial cells, (especially astrocytes) can desaturate and elongate dietary ALA to convert it into DHA, which is subsequently transferred to most neurons [104,105]. DHA can also modulate the expression of genes related to neuronal energy generation involved in the function of the respiratory chain and ATP synthesis (adenosine triphosphate synthase) [103,104,105]. That function is relevant because approximately 50% of mitochondrial ATP is consumed by the Na+/K+ ATPase pump to maintain cell homeostasis and ionic gradients, a fundamental requirement for neuronal electrical excitability [103,104,105].

As already mentioned, AA is one of the most abundant fatty acids in the brain [26]. This n-6 LCPUFA is indispensable for brain growth and modulation of cell division and signaling [29]. During brain development, the concentration of AA increases rapidly [106]. It has been described in animal models that approximately 70–80% of AA concentration that is reached in adulthood is the result of its cerebral accumulation in the early postnatal period [2]. AA is an immediate precursor of adrenic acid (C22:4n-6, AdA), fatty acid found in large amounts in myelinic lipids, especially in phosphatidylethanolamine and phosphatidylcholine [106,107], suggesting the fundamental role of AA as a precursor of AdA in the development of neural tissue [106]. Conversion of AA to AdA may represent an important mechanism for supplying the high demand for AdA at the brain level, which is essential for neuronal myelinic lipid enrichment [2,106]. Wijendran et al. (2002) [108] investigated the metabolism of preformed AA in newborn baboons by the administration of a single oral dose of C¹³-labeled AA, reporting that 79–93% of AA consumed accumulates in brain membrane lipids and approximately 5% to 16% of AA is transformed into AdA [108]. Brain accumulation of AA and AdA occurs during the first month of life and represent 17% and 8% of the total n-6 LCPUFA, respectively [108].

Another brain function of AA is directly related to its participation in phosphatidylcholine (PC) structure [107]. Some intracellular phospholipid bilayers include AA-containing PC (AA-PC), a structure that plays a role as second messenger participating in the long-term enhancement of synapses in the CA1 region of the hippocampus [109]. Using image mass spectrometry, Yang et al. (2012) [110] characterized the distribution of AA-PC within neurons in cultured upper cervical nodes, finding an increasing gradient of AA-PC along the proximal to distal axonal axis suggesting that this structure is an important source of free AA [110]. Furthermore, it has been described that free AA can activate protein kinases and ion channels and inhibit neurotransmitter recycling [29], thus contributing to better control of synaptic transmission [70]. In addition to the role of AA in modulating neuronal excitability, AA is also essential in neuronal development in part because it is directly responsible for the activation of syntaxin-3, a protein of the neuronal membrane involved in the growth and neurite repair, an essential process in neurogenesis and subsequently in synaptic transmission [111].

Remarkably, LCPUFA levels in the brain are highly correlated with dietary intake of PUFA and LCPUFA [112]. DHA and AA are precursors of many bioactive lipid mediators identified as docosanoids and eicosanoids, respectively, which are actively involved in regulatory responses in inflammation (eicosanoids such as prostaglandins, prostacyclins, thromboxanes, leucotrienes) and in resolution of inflammation (docosanoids such as resolvins and maresins) [113]. Both LCPUFA are also involved in the formation of endocannabinoids (eCB) with regulatory effects at the central nervous system (CNS) [114]. The endocannabinoid system consists of eCB, eCB receptors CB1 and CB2, and associated anabolic and catabolic enzymes [115]. Their functions are to maintain body energy homeostasis through the nutrient availability detection and the modulation of orexinergic inputs in selective regions of the CNS [116]. PUFA derived eicosanoids and eCB have been identified as independent ligands of CB1 and CB2 receptors [115]. Hammels et al. (2019) [115] reported that CB1 ligands synthesis in CNS depends on dietary intake of AA and DHA in a model of fatty acid desaturase 2-deficient mouse [115]. Moreover, DHA and AA have been recognized as ligands of the nuclear RxR receptor in the brain, being the PUFA ratio in the western diet, a critical nutritional parameter for numerous neurodegenerative diseases [115], which could increase neuroinflammation and over-stimulation of the endocannabinoid system [117]. AA bound to phospholipids determines the formation of eCB, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), molecules involved in the regulation of neuroinflammatory responses by microglia and astrocytes [114]. On the contrary, long-term supplementation with DHA and EPA reduces AEA and 2-AG synthesis [118]. N-3 and n-6 PUFA derived eCB are synthesized by lipoxygenases (LOX), cyclooxygenase 2 (COX-2), and cytochrome P450 epoxygenases (CYP450). Nevertheless, only LOX and CYP450 metabolites have been reported for a DHA eCB derivative; n-docosahexaenoylethanolamide (DHEA), and only CYP450 metabolites for an EPA eCB derivative; eicosapentaenoyl ethanolamide (EPEA) [116]. The physiological role of the metabolites generated by LOX and CYP450 remains to be elucidated to understand how these derivatives modulate cell signaling in health and disease [116]. A better understanding of the relationship between DHA, AA, and the endocannabinoid system is expected to lead to advances in the development of their therapeutic potential and the development of more specific treatment options for the prevention and treatment of neurodegenerative diseases [114].