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Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.
Morgan AJ, Kingsley PJ, Mitchener MM, Altemus M, Patrick TA, Gaulden AD, Marnett LJ, Patel S
(2018) ACS Chem Neurosci 9: 1552-1559
MeSH Terms: Animals, Arachidonic Acids, Brain, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Endocannabinoids, Esters, Female, Glycerides, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Monoacylglycerol Lipases, Neurons, Oxidation-Reduction, Prostaglandins
Show Abstract · Added October 8, 2018
Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
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18 MeSH Terms
Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Bedse G, Bluett RJ, Patrick TA, Romness NK, Gaulden AD, Kingsley PJ, Plath N, Marnett LJ, Patel S
(2018) Transl Psychiatry 8: 92
MeSH Terms: Amidohydrolases, Animals, Anti-Anxiety Agents, Anxiety Disorders, Behavior, Animal, Benzodioxoles, Body Temperature, Brain, Carbamates, Endocannabinoids, Female, Locomotion, Male, Maze Learning, Mice, Inbred C57BL, Mice, Inbred ICR, Monoacylglycerol Lipases, Piperazines, Piperidines, Pyridines, Stress, Psychological
Show Abstract · Added April 12, 2019
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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MeSH Terms
Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking.
Holleran KM, Wilson HH, Fetterly TL, Bluett RJ, Centanni SW, Gilfarb RA, Rocco LE, Patel S, Winder DG
(2016) Neuropsychopharmacology 41: 2062-71
MeSH Terms: Affect, Alcohol Drinking, Animals, Behavior, Animal, Benzodioxoles, Depression, Endocannabinoids, Ethanol, Excitatory Amino Acid Antagonists, Female, Ketamine, Mice, Inbred C57BL, Monoacylglycerol Lipases, Piperidines
Show Abstract · Added March 14, 2018
Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.
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14 MeSH Terms
The serine hydrolase ABHD6 Is a critical regulator of the metabolic syndrome.
Thomas G, Betters JL, Lord CC, Brown AL, Marshall S, Ferguson D, Sawyer J, Davis MA, Melchior JT, Blume LC, Howlett AC, Ivanova PT, Milne SB, Myers DS, Mrak I, Leber V, Heier C, Taschler U, Blankman JL, Cravatt BF, Lee RG, Crooke RM, Graham MJ, Zimmermann R, Brown HA, Brown JM
(2013) Cell Rep 5: 508-20
MeSH Terms: Amino Acid Sequence, Animals, Diet, High-Fat, Endocannabinoids, Fatty Acids, Humans, Liver, Male, Metabolic Syndrome, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Monoacylglycerol Lipases, Obesity, Oligonucleotides, Antisense, Receptor, Cannabinoid, CB1, Sequence Alignment, Signal Transduction
Show Abstract · Added March 7, 2014
The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6's role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats.
Rivera P, Luque-Rojas MJ, Pastor A, Blanco E, Pavón FJ, Serrano A, Crespillo A, Vida M, Grondona JM, Cifuentes M, Bermúdez-Silva FJ, de la Torre R, de Fonseca FR, Suárez J
(2013) Eur J Neurosci 37: 105-17
MeSH Terms: Amidohydrolases, Animals, Arachidonic Acids, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists, Diet, High-Fat, Dietary Carbohydrates, Dietary Fats, Endocannabinoids, Hippocampus, Lipoprotein Lipase, Male, Monoacylglycerol Lipases, Obesity, Phospholipase D, Piperidines, Polyunsaturated Alkamides, Pyrazoles, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1, Weight Gain
Show Abstract · Added April 10, 2014
Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.
© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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22 MeSH Terms
Reversible gating of endocannabinoid plasticity in the amygdala by chronic stress: a potential role for monoacylglycerol lipase inhibition in the prevention of stress-induced behavioral adaptation.
Sumislawski JJ, Ramikie TS, Patel S
(2011) Neuropsychopharmacology 36: 2750-61
MeSH Terms: Adaptation, Psychological, Amygdala, Animals, Anxiety Disorders, Arachidonic Acids, Benzodioxoles, Cannabinoid Receptor Modulators, Chronic Disease, Disease Models, Animal, Endocannabinoids, Glycerides, Male, Mice, Mice, Inbred ICR, Monoacylglycerol Lipases, Organ Culture Techniques, Piperidines, Stress, Psychological
Show Abstract · Added January 20, 2015
Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.
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18 MeSH Terms
Endocannabinoid dysregulation in the pancreas and adipose tissue of mice fed with a high-fat diet.
Starowicz KM, Cristino L, Matias I, Capasso R, Racioppi A, Izzo AA, Di Marzo V
(2008) Obesity (Silver Spring) 16: 553-65
MeSH Terms: Adipose Tissue, Age Factors, Amidohydrolases, Animals, Arachidonic Acids, Blood Glucose, Body Weight, Cannabinoid Receptor Modulators, Chromatography, Liquid, Dietary Fats, Disease Models, Animal, Endocannabinoids, Fluorescent Antibody Technique, Glycerides, Hyperglycemia, Lipoprotein Lipase, Male, Mass Spectrometry, Mice, Mice, Inbred C57BL, Monoacylglycerol Lipases, Obesity, Pancreas, Phospholipase D, Polyunsaturated Alkamides, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Time Factors
Show Abstract · Added April 10, 2014
OBJECTIVE - In mice, endocannabinoids (ECs) modulate insulin release from pancreatic beta-cells and adipokine expression in adipocytes through cannabinoid receptors. Their pancreatic and adipose tissue levels are elevated during hyperglycemia and obesity, but the mechanisms underlying these alterations are not understood.
METHODS AND PROCEDURES - We assessed in mice fed for up to 14 weeks with a standard or high-fat diet (HFD): (i) the expression of cannabinoid receptors and EC biosynthesizing enzymes (N-acyl-phosphatidyl-ethanolamine-selective phospholipase D (NAPE-PLD) and DAGLalpha) and degrading enzymes (fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)) in pancreatic and adipose tissue sections by immunohistochemical staining; (ii) the amounts, measured by liquid chromatography-mass spectrometry, of the ECs, 2-AG, and anandamide (AEA).
RESULTS - Although CB(1) receptors and biosynthetic enzymes were found mostly in alpha-cells, degrading enzymes were identified in beta-cells. Following HFD, staining for biosynthetic enzymes in beta-cells and lower staining for FAAH were observed together with an increase of EC pancreatic levels. While we observed no diet-induced change in the intensity of the staining of EC metabolic enzymes in the mesenteric visceral fat, a decrease in EC concentrations was accompanied by lower and higher staining of biosynthesizing enzymes and FAAH, respectively, in the subcutaneous fat. No change in cannabinoid receptor staining was observed following HFD in any of the analyzed tissues.
DISCUSSION - We provide unprecedented information on the distribution of EC metabolic enzymes in the pancreas and adipose organ, where their aberrant expression during hyperglycemia and obesity contribute to dysregulated EC levels.
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28 MeSH Terms
Hydrolysis of prostaglandin glycerol esters by the endocannabinoid-hydrolyzing enzymes, monoacylglycerol lipase and fatty acid amide hydrolase.
Vila A, Rosengarth A, Piomelli D, Cravatt B, Marnett LJ
(2007) Biochemistry 46: 9578-85
MeSH Terms: Amidohydrolases, Animals, Brain, Dinoprostone, Dogs, Hydrolysis, Mice, Monoacylglycerol Lipases, Substrate Specificity
Show Abstract · Added March 5, 2014
Cyclooxygenase-2 (COX-2) can oxygenate the endocannabinoids, arachidonyl ethanolamide (AEA) and 2-arachidonylglycerol (2-AG), to prostaglandin-H2-ethanolamide (PGH2-EA) and -glycerol ester (PGH2-G), respectively. Further metabolism of PGH2-EA and PGH2-G by prostaglandin synthases produces a variety of prostaglandin-EA's and prostaglandin-G's nearly as diverse as those derived from arachidonic acid. Thus, COX-2 may regulate endocannabinoid levels in neurons during retrograde signaling or produce novel endocannabinoid metabolites for receptor activation. Endocannabinoid-metabolizing enzymes are important regulators of their action, so we tested whether PG-G levels may be regulated by monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH). We found that PG-Gs are poor substrates for purified MGL and FAAH compared to 2-AG and/or AEA. Determination of substrate specificity demonstrates a 30-100- and 150-200-fold preference of MGL and FAAH for 2-AG over PG-Gs, respectively. The substrate specificity of AEA compared to those of PG-Gs was approximately 200-300 fold higher for FAAH. Thus, PG-Gs are poor substrates for the major endocannabinoid-degrading enzymes, MGL and FAAH.
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9 MeSH Terms