Membrane microdomains and metabolic pathways that define anandamide and 2-arachidonyl glycerol biosynthesis and breakdown

Cooper

Journal of Pharmaceutical and Biomedical Analysis

et al. 2010

Self Cite

Elucidation of pathways involved with lipid metabolism has been limited by analytical challenges associated with detection and structure identification. A discovery-based mass spectrometry lipidomic approach has been applied to identify metabolites of the endogenous cannabinoid anandamide (N-arachidonylethanolamide). Previously, a model system was established to show that anandamide can be recycled by cells to form new endocannabinoids suggesting recycling of the arachidonate carbon chain. We hypothesized that distinct cellular pathways exist to direct the anandamide-derived arachidonate chain into a specific set of metabolites, different from the metabolite pool that is comprised of non-anandamide-derived arachidonic acid. Using stable isotope encoding and liquid chromatography-mass spectrometry, we identified a distinct pool of lipid metabolites derived from exogenous anandamide or arachidonic acid in RBL-2H3 cells. We discovered that arachidonic acid-derived metabolites were primarily comprised of the eicosanoid lipid class, whereas anandamide-derived arachidonic acid, in addition to eicosanoids, was metabolized into diradylglycerols, fatty acid amides, sterols, and glycerophospholipids. From the list of anandamide metabolites of particular interest was 1-O-arachidonyl-sn-glycero-3-phosphocholine. Furthermore, we determined that while 1-O-arachidonyl-sn-glycero-3-phosphocholine may be a metabolite of anandamide, the sn-2 compound was more abundant in mouse brain tissue. Overall, our results provide a novel approach to study the metabolic fate of endocannabinoids and fatty acid-derived signaling molecules.

Section: Resultsmentioning

confidence: 99%

Lipidomic metabolism analysis of the endogenous cannabinoid anandamide (N-arachidonylethanolamide)

Cooper

Journal of Pharmaceutical and Biomedical Analysis

et al. 2010

Self Cite

Cannabinoids in Health and Disease

“…FAAH is situated in the intracellular compartment and is bound to membranes, which can modulate the access of AEA to its degradation enzyme [71]. Drugs targeting the FAAH enzyme have been extensively studied for the treatment of endocannabinoids-related disorders, such as anxiety, depression, inflammation or neuropathic pain [72].…”

Section: Aea Metabolismmentioning

confidence: 99%

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

Bosch‐Bouju¹,

Layé²

2016

Omega-3 (ω-3) and omega-6 (ω-6) are polyunsaturated fatty acids (PUFAs) that play critical role in human health and have to be provided by food. In the brain, PUFAs are also precursors of endocannabinoids. The aim of this chapter is to review the existing literature on how dietary PUFAs impact on the endocannabinoid system in the brain and what are the consequences for brain function and dysfunction. In this chapter, we will first describe how PUFAs enter the brain, what are their metabolism processes and roles in brain function. We will describe the pathways from PUFAs to endocannabinoid production. Then, we will review the literature on how dietary ω-6/ω-3 ratio impacts the endocannabinoid system, in terms of endocannabinoid levels, proteins and endocannabinoid-dependent synaptic plasticity. In the next part, we will describe what we know about the interactions between PUFAs and endocannabinoids in neurological and neuropsychiatric disorders. Finally, we will conclude on the possible implications of the interactions between dietary PUFAs and endocannabinoids in the normal and pathological brain. In particular, we will discuss how dietary PUFAs, as homeostatic regulators of endocannabinoids, can constitute interesting therapeutic strategies for the prevention and/or treatment of neurological disorders with endocannabinoids impairment.

“…The hydrolysis of AEA releases ARA and ethanolamine and is principally achieved by the fatty acid amide hydrolase (FAAH) enzyme [84], although further yet to be identified proteins are likely involved in the process [61]. DHEA is also a substrate for FAAH hydrolysis to release DHA and ethanolamine [68], whereas the process of EPEA hydrolysis has yet to be identified.…”

Section: Metabolism Of Pufa and Endocannabinoidsmentioning

confidence: 99%

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

Dyall

2017

Lipids

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.