Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist

Deutsch, Dale G.; Chin, Suzette A.

doi:10.1016/0006-2952(93)90486-g

Cited by 657 publications

(502 citation statements)

References 15 publications

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“…This metabolism will function to reduce the AEA gradient across the cell membrane. PMSF (or indeed N-ethylmaleimide), by acting as an inhibitor of FAAH (Deutsch & Chin, 1993;Bisogno et al, 1997), will increase the level of unmetabolized AEA and hence the gradient, making uptake against the gradient more di cult. Indeed, Rakhshan et al (2000) found that two other FAAH inhibitors (arachidonoyl tri¯uoromethylketone, methyl arachidonoyl¯uorophosphonate) reduced the uptake of [ 3 H]-AEA into RBL-2H3 cells more e ectively than PMSF.…”

Section: Discussionmentioning

confidence: 99%

“…This process includes cellular uptake and intracellular degradation by the enzyme fatty acid amide hydrolase (FAAH) (Deutsch & Chin, 1993;Di Marzo et al, 1994). Cellular uptake of AEA has been demonstrated and characterized in neural-derived cell lines (Deutsch & Chin, 1993;Piomelli et al, 1999), primary cultures of cerebellar granule cells (Hillard et al, 1997), striatal neurons and astrocytes (Di Marzo et al, 1994;Beltramo et al, 1997), as well as in the immortalized rat basophilic leukaemia cell line RBL-2H3 (Bisogno et al, 1997;Rakhshan et al, 2000). The uptake mechanism has been shown to be mediated by a saturable, selective, temperature-dependent and Na + -independent transporter (Di Marzo et al, 1994;Beltramo et al, 1997;Hillard et al, 1997), supporting the hypothesis that the AEA uptake is carrier-mediated.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide

Jacobsson

Fowler

2001

British J Pharmacology

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1 The endogenous cannabinoid receptor agonist anandamide (AEA) and the related compound palmitoylethanolamide (PEA) are inactivated by transport into cells followed by metabolism by fatty acid amide hydrolase (FAAH). The cellular uptake of AEA has been characterized in detail, whereas less is known about the properties of the PEA uptake, in particular in neuronal cells. In the present study, the pharmacological and functional properties of PEA and AEA uptake have been investigated in mouse Neuro-2a neuroblastoma and, for comparison, in rat RBL-2H3 basophilic leukaemia cells. 2 Saturable uptake of PEA and AEA into both cell lines were demonstrated with apparent K M values of 28 mM (PEA) and 10 mM (AEA) in Neuro-2a cells, and 30 mM (PEA) and 9.3 mM (AEA) in RBL-2H3 cells. Both PEA and AEA uptake showed temperature-dependence but only the AEA uptake was sensitive to treatment with Pronase and phenylmethylsulfonyl¯uoride. 3 The AEA uptake was inhibited by AM404, 2-arachidonoylglycerol (2-AG), R1-and S1-methanandamide, arachidonic acid and olvanil with similar potencies for the two cell types. PEA, up to a concentration of 100 mM, did not a ect AEA uptake in either cell line. AEA, 2-AG, arachidonic acid, R1-methanandamide, D 9 -THC, and cannabidiol inhibited PEA transport in both cell lines. The non-steroidal anti-in¯ammatory drug indomethacin inhibited the AEA uptake but had very weak e ects on the uptake of PEA. 4 From these data, it can be concluded that PEA is transported in to cells both by passive di usion and by a facilitated transport that is pharmacologically distinguishable from AEA uptake.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide

Jacobsson

Fowler

2001

British J Pharmacology

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“…1). Since cells lacking NAPEphospholipase D are also able to synthesise anandamide, alternative pathways have been proposed (41)(42)(43)(44)(45)(46)(47) and they are summarised in Fig. 1.…”

Section: Endocannabinoids Biosynthesis and Uptakementioning

confidence: 99%

PUFA-derived endocannabinoids: an overview

Cascio

2013

Proc. Nutr. Soc.

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Following on from the discovery of cannabinoid receptors, of their endogenous agonists (endocannabinoids) and of the biosynthetic and metabolic enzymes of the endocannabinoids, significant progress has been made towards the understanding of the role of the endocannabinoid system in both physiological and pathological conditions. Endocannabinoids are mainly n-6 long-chain PUFA (LCPUFA) derivatives that are synthesised by neuronal cells and inactivated via a two-step process that begins with their transport from the extracellular to the intracellular space and culminates in their intracellular degradation by hydrolysis or oxidation. Although the enzymes responsible for the biosynthesis and metabolism of endocannabinoids have been well characterised, the processes involved in their cellular uptake are still a subject of debate. Moreover, little is yet known about the roles of endocannabinoids derived from n-3 LCPUFA such as EPA and DHA. Here, I provide an overview of what is currently known about the mechanisms for the biosynthesis and inactivation of endocannabinoids, together with a brief analysis of the involvement of the endocannabinoids in both food intake and obesity. Owing to limited space, recent reviews will be often cited instead of original papers.

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“…N-Arachidonoylethanolamine, termed 'anandamide' [1], was also shown to inhibit both adenylate cyclase [5] and calcium currents [6], and to display other pharmacologic activities [7][8][9]. As potentially psychoactive agents, long-chain polyunsaturated NAEs would be expected to be readily generated and degraded, perhaps by direct N-acylation and deacylation of ethanolamine [10][11][12][13][14][15], and to be present only in trace amounts in vivo. However, postdecapitative cerebral ischemia is known to cause a rapid rise in free fatty acid levels in rat brain [16][17][18][19], including the polyunsaturated fatty acids 20: 3n-6, 20: 4n-6 and 22 : 6n-6, all of which have been found as ethanolamides in pig brain extracts [1,2].…”

Section: Introductionmentioning

confidence: 99%

Occurrence and postmortem generation of anandamide and other long‐chain N‐acylethanolamines in mammalian brain

et al. 1995

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Long-chain N-acylethanolamines (NAEs) were assayed in pig, sheep and cow brain by gas chromatography/mass spectrometry of their tert.-butyldimethylsilyl derivatives in the presence of deuterium-labeled internal standards. Immediately after death, total NAEs ranged from about 2.7/tglg wet weight (sheep, cow) to 6.5 /tg/g wet weight (pig) and consisted almost exclusively (99%) of saturated and monounsaturated species. Anandamide (20:4n-6 NAE) comprised about 1% of total NAE in pig and cow brain, but was absent in freshly extracted sheep brain. When pig brain was analysed after 0.5, 1, 3, 4 and 23 h at ambient temperature, NAE levels were found to increase substantially over the entire time period with 20:4n-6 NAE formation exhibiting a time lag compared to that of saturated and monounsaturated NAEs.Key words: N-Acylethanolamine; Anandamide; Arachidonic acid; Pig brain; Sheep brain; Cow brain dog heart [20,21] and have observed that N-acylethanolamine phospholipids are generated in young rat brain within 15 min postmortem [19]. In mammalian cells, N-acylethanolamine phospholipids are produced by acyl transfer from the sn-1 position of various glycerophospholipids to the free amino group of ethanolamine phospholipids [22][23][24], a reaction that does not involve ester hydrolysis [25]. They are metabolized to N-acylethanolamines and phosphatidic acid by phosphodiesterase (phospholipase D) activity [26,27]. This pathway generates primarily saturated and monounsaturated, as well as some diunsaturated [28], NAEs and these are the only ones for which quantitative information is available [29].Here, we report the quantitative assay of NAEs present in pig, sheep and cow brain at different periods postmortem using gas chromatography-mass spectrometry of their tert.-butyldimethylsilyl derivatives in the presence of deuterated analogs as internal standards.

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Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist

Cited by 657 publications

References 15 publications

Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide

Characterization of palmitoylethanolamide transport in mouse Neuro‐2a neuroblastoma and rat RBL‐2H3 basophilic leukaemia cells: comparison with anandamide

PUFA-derived endocannabinoids: an overview

Occurrence and postmortem generation of anandamide and other long‐chain N‐acylethanolamines in mammalian brain

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