Interplay Between n‐3 and n‐6 Long‐Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair

Abstract

The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

Effects of Cannabis Use on the Protein and Lipid Profile of Olfactory Neuroepithelium Cells from Schizophrenia Patients Studied by Synchrotron-Based FTIR Spectroscopy

“…In contrast, an increase in the 3016 cm −1 peak was observed in all subjects that smoke cannabis (HC/c and in SCZ/c), indicating an increase in long-chain polyunsaturated lipid mediators, such as docosahexaenoic acid (DHA), arachidonic acid (ARA), or endocannabinoids (AEA and 2-AG) [38]. Endocannabinoids have complex actions depending on which receptors or brain structure, they target, including modulation of mood and memory processes, as well as neuroinflammation and energy metabolism homeostasis [44]. In frequent cannabis users, lower levels of AEA in cerebrospinal fluid, and higher levels of 2-AG in serum were observed as compared to infrequent cannabis users, and higher levels of AEA were associated with a lower risk of psychotic symptoms following cannabis use [45].…”

Ovarian Function Modulates the Effects of Long-Chain Polyunsaturated Fatty Acids on the Mouse Cerebral Cortex

“…Experimental evidence has suggested that the ratio between n −6 and n −3 LC-PUFAs is a critical factor for their developmental and neuroprotective activity (Miller et al, 2016 ; Dyall, 2017 ). Therefore, the present study tested the effects of two experimental diets, DI and DII, whose major difference in composition was the global ratio of n −6 and n −3 LC-PUFAs.…”

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease

“…The eCB system has been shown to play an important role in neuroprotective and pro-neurogenic processes, such as the attenuation of neuroinflammation, regulation of pro-inflammatory cytokine release, and increased synaptic plasticity and neurogenesis [132]. Since eCBs are lipid signaling agents produced from LC-PUFAs, strong evidence suggests that diet may lead to a change in the eCB system neuroinflammatory signaling [133,134]. Because of their fundamental nature, AA, DHA, their respective mediators and the eCB system have a large spectrum of effects on the CNS, and recent evidence strongly indicates a complex interaction among them.…”

“…In the CNS, eCBs are produced by neurons and glial cells, and appear to play a key role in synaptic plasticity and neuroimmune networks [138]. Recent studies have shown that brain levels of LC-PUFAs respond to diet and the ratio of n-6 FA over n-3 FA intake [133]. Alvheim et al showed, in animal models, that diets rich in n-6 FA elevate the levels of 2-AG and AEA [139].…”