The Multiple Pathways of Endocannabinoid Metabolism: A Zoom Out

Vandevoorde, Séverine; Lambert, Didier M.

doi:10.1002/cbdv.200790156

Cited by 34 publications

(18 citation statements)

References 216 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the other endocannabinoids, see a specific review (47). Because endocannabinoid metabolism has been extensively discussed by several other reviews (21,38,402,492,536), we will refer only to representative studies.…”

Section: A Endocannabinoidsmentioning

confidence: 99%

“…Endocannabinoids can be degraded through two different pathways, hydrolysis and oxidation (536). The enzymes that catalyze the first pathway include fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MGL) for 2-AG.…”

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

“…MGL is now recognized as the main enzyme catalyzing the hydrolysis of 2-AG in vivo (128,129,536). Mouse, rat, and human MGL proteins are all 303 amino acids in length (128,257,258).…”

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

“…Among them, COX-1 and COX-2 preferably recognize arachidonic acid (AA) as a substrate. When incubated with anandamide, purified COX-2, but not COX-1, acts on anandamide and produces prostaglandin-ethanolamides, although the affinity for anandamide is lower than that for AA (536). In contrast, 2-AG is a substrate as effective as AA for COX-2 (536).…”

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

See 3 more Smart Citations

Endocannabinoid-Mediated Control of Synaptic Transmission

Kano¹,

Ohno‐Shosaku²,

Hashimotodani³

et al. 2009

Physiological Reviews

1,318

1,431

View full text Add to dashboard Cite

The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for cannabinoid research and also established a new concept how diffusible messengers modulate synaptic efficacy and neural activity. The last 7 years have witnessed remarkable advances in our understanding of the endocannabinoid system. It is now well accepted that endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid CB1 receptors, and cause transient and long-lasting reduction of neurotransmitter release. In this review, we aim to integrate our current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain. We summarize recent electrophysiological studies carried out on synapses of various brain regions and discuss how synaptic transmission is regulated by endocannabinoid signaling. Then we refer to recent anatomical studies on subcellular distribution of the molecules involved in endocannabinoid signaling and discuss how these signaling molecules are arranged around synapses. In addition, we make a brief overview of studies on cannabinoid receptors and their intracellular signaling, biochemical studies on endocannabinoid metabolism, and behavioral studies on the roles of the endocannabinoid system in various aspects of neural functions.

show abstract

Section: A Endocannabinoidsmentioning

confidence: 99%

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

“…MGL is now recognized as the main enzyme catalyzing the hydrolysis of 2-AG in vivo (128,129,536). Mouse, rat, and human MGL proteins are all 303 amino acids in length (128,257,258).…”

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

Section: Degradation Of Endocannabinoidsmentioning

confidence: 99%

See 2 more Smart Citations

Endocannabinoid-Mediated Control of Synaptic Transmission

Kano¹,

Ohno‐Shosaku²,

Hashimotodani³

et al. 2009

Physiological Reviews

1,318

1,431

View full text Add to dashboard Cite

show abstract

“…Endogenous levels of AEA and 2-AG can be elevated through inactivation of their metabolizing enzymes: fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively [23][24][25][26]. In the brain, FAAH has been localized postsynaptically within the somata of hippocampal pyramidal cells, granule cells of the dentate gyrus, Purkinje cells of the cerebellum, and neocortical neuronal cell bodies [23,27,28].…”

Section: Introductionmentioning

confidence: 99%

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

et al. 2012

View full text Add to dashboard Cite

Advances in the understanding of the endogenous cannabinoid system have led to several therapeutic indications for new classes of compounds that enhance cannabinergic responses. Endocannabinoid levels are elevated during pathogenic conditions, and inhibitors of endocannabinoid inactivation promote such on-demand responses. The endocannabinoids anandamide and 2-arachidonoyl glycerol have been implicated in protective signaling against excitotoxic episodes, including seizures. To better understand modulatory pathways that can exploit such responses, we used the new generation compound AM6701 that blocks both the anandamide-deactivating enzyme fatty acid amide hydrolase (FAAH) and the 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase (MAGL) with equal potency. Also studied was the structural isomer AM6702 which is 44-fold more potent for inhibiting FAAH versus MAGL. When applied before and during kainic acid (KA) exposure to cultured hippocampal slices, AM6701 protected against the resulting excitotoxic events of calpain-mediated cytoskeletal damage, loss of presynaptic and postsynaptic proteins, and pyknotic changes in neurons. The equipotent inhibitor was more effective than its close relative AM6702 at protecting against the neurodegenerative cascade assessed in the slice model. In vivo, AM6701 was also the more effective compound for reducing the severity of KA-induced seizures and protecting against behavioral deficits linked to seizure damage. Corresponding with the behavioral improvements, cytoskeletal and synaptic protection was elicited by AM6701, as found in the KA-treated hippocampal slice model. It is proposed that the influence of AM6701 on FAAH and MAGL exerts a synergistic action on the endocannabinoid system, thereby promoting the protective nature of cannabinergic signaling to offset excitotoxic brain injury.

show abstract

Aging modifies the enzymatic activities involved in 2‐arachidonoylglycerol metabolism

et al. 2012

View full text Add to dashboard Cite

One of the principal monoacylglycerol (MAG) species in animal tissues is 2-arachidonoylglycerol (2-AG), and the diacylglycerol lipase (DAGL) pathway is the most important 2-AG biosynthetic pathway proposed to date. Lysophosphatidate phosphatase (LPAase) activity is part of another 2-AG-forming pathway in which monoacylglycerol lipase (MAGL) is the major degrading enzyme. The purpose of this study was to analyze the manner in which DAGL, LPAase, and MAGL enzymes are modified in the central nervous system (CNS) during aging. To this end, diacylglycerols (DAGs) and MAGs of different composition were used as substrates of DAGL and MAGL, respectively. All enzymatic activities were evaluated in membrane and soluble fractions as well as in synaptic terminals from the cerebral cortex (CC) of adult and aged rats. Results related to 2-AG metabolism show that aging: (a) decreases DAGL-α expression in the membrane fraction whereas in synaptosomes it increases DAGL-β and decreases MAGL expression; (b) decreases LPAase activity in both membrane and soluble fractions; (c) decreases DAGL and stimulates LPAase activities in CC synaptic terminals; (d) stimulates membrane-associated MAGL-coupled DAGL activity; and (e) stimulates MAGL activity in CC synaptosomes. Our results also reveal that during aging the net balance between the enzymatic activities involved in 2-AG synthesis and breakdown is low availability of 2-AG in CC membrane fractions and synaptic terminals. Taken together, our results lead us to conclude that these enzymes play crucial roles in the regulation of 2-AG tissue levels during aging.

show abstract

The Multiple Pathways of Endocannabinoid Metabolism: A Zoom Out

Cited by 34 publications

References 216 publications

Endocannabinoid-Mediated Control of Synaptic Transmission

Endocannabinoid-Mediated Control of Synaptic Transmission

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

Aging modifies the enzymatic activities involved in 2‐arachidonoylglycerol metabolism

Contact Info

Product

Resources

About