Activation of the endocannabinoid system by organophosphorus nerve agents

Nomura, Daniel K.; Blankman, Jacqueline L.; Simón, Gabriel; Fujioka, Kazutoshi; Issa, Roger S.; Ward, Anna M.; Cravatt, Benjamin F.; Casida, John E.

doi:10.1038/nchembio.86

Cited by 109 publications

(134 citation statements)

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“…Although hepatic CB1 activation probably is the target of our observed effects, we cannot exclude centrally mediated actions upon peripheral tissues because brain EC levels are elevated as well (18). However, the ablation of TG elevation in apoEϪ/Ϫ mice even in the presence of full-blown cannabinoid behavioral effects (observed in this study in IDFPtreated apoEϩ/ϩ and Ϫ/Ϫ mice and ref.…”

Section: Discussionmentioning

confidence: 68%

“…However, the ablation of TG elevation in apoEϪ/Ϫ mice even in the presence of full-blown cannabinoid behavioral effects (observed in this study in IDFPtreated apoEϩ/ϩ and Ϫ/Ϫ mice and ref. 18) strongly argues that the CB1-mediated hypertriglyceridemia and apoE effects are mediated peripherally. The development of peripheral CB1 antagonists that do not cross the blood-brain barrier and tissue-specific CB1Ϫ/Ϫ mouse models (13) will aid in addressing this issue.…”

Section: Discussionmentioning

confidence: 99%

“…The ECs anandamide and 2-arachidonoylglycerol (2-AG) are produced locally by N-acyl phosphatidylethanolamine phospholipase D and by diacylglycerol lipase, respectively (14,15). Signaling is terminated primarily by enzymatic breakdown of anandamide by fatty acid amide hydrolase (FAAH) and of 2-AG by monoacylglycerol lipase (MAGL) (14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

“…The organophosphorus compound isopropyl dodecylfluorophosphonate (IDFP) inhibits both MAGL and FAAH in vivo in mice, raises brain 2-AG and anandamide levels by more than 10-fold, and elicits full-blown cannabinoid behavior (18). CB1-mediated effects of IDFP can be clearly differentiated from off-target actions by reversal with a specific CB1 antagonist and by their absence in CB1Ϫ/Ϫ mice (18). This study determined the effects of IDFP-induced overactive EC signaling and CB1 agonism on lipid metabolism, independent of adiposity or food intake.…”

mentioning

confidence: 99%

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Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

Ruby¹,

Nomura

Hudak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The endocannabinoid (EC) system regulates food intake and energy metabolism. Cannabinoid receptor type 1 (CB1) antagonists show promise in the treatment of obesity and its metabolic consequences. Although the reduction in adiposity resulting from therapy with CB1 antagonists may not account fully for the concomitant improvements in dyslipidemia, direct effects of overactive EC signaling on plasma lipoprotein metabolism have not been documented. The present study used a chemical approach to evaluate the direct effects of increased EC signaling in mice by inducing acute elevations of endogenously produced cannabinoids through pharmacological inhibition of their enzymatic hydrolysis by isopropyl dodecylfluorophosphonate (IDFP). Acute IDFP treatment increased plasma levels of triglyceride (TG) (2.0-to 3.1-fold) and cholesterol (1.3-to 1.4-fold) in conjunction with an accumulation in plasma of apolipoprotein (apo)E-depleted TG-rich lipoproteins. These changes did not occur in either CB1-null or apoE-null mice, were prevented by pretreatment with CB1 antagonists, and were not associated with reduced hepatic apoE gene expression. Although IDFP treatment increased hepatic mRNA levels of lipogenic genes (Srebp1 and Fas), there was no effect on TG secretion into plasma. Instead, IDFP treatment impaired clearance of an intravenously administered TG emulsion, despite increased postheparin lipoprotein lipase activity. Therefore, overactive EC signaling elicits an increase in plasma triglyceride levels associated with reduced plasma TG clearance and an accumulation in plasma of apoE-depleted TG-rich lipoproteins. These findings suggest a role of CB1 activation in the pathogenesis of obesity-related hypertriglyceridemia and underscore the potential efficacy of CB1 antagonists in treating metabolic disease.2-arachidonoylglycerol ͉ hypertriglyceridemia ͉ monoaylglycerol lipase ͉ organophosphorus ͉ cannabinoid receptor O besity elicits a cluster of interrelated disorders, termed the ''metabolic syndrome,'' that increases the risk of cardiovascular disease (1). Epidemiological and genetic data indicate that dysregulation of the endocannabinoid (EC) system increases adiposity in humans (2-4). Pharmacological or genetic ablation of the cannabinoid type 1 receptor (CB1) in normal mice and in diet-induced and genetic mouse models of obesity results in a transient hypophagic response mediated through the hypothalamus, but there also are prolonged effects on weight loss, adiposity, and normalization of metabolic parameters, including plasma lipids (5-11). These effects suggest that the improvement in adiposity-related measures with CB1 inactivation is not limited to reduced food intake, a major known effect of CB1 inactivation (5, 11). CB1 activation in liver increases de novo lipogenesis and decreases fatty acid oxidation (12, 13). High-fat diet or chronic ethanol treatment increases cannabinoid signaling tone via increased hepatic CB1 receptor density and EC levels leading to CB1-mediated hepatic steatosis (12, 13). These observations...

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

Ruby¹,

Nomura

Hudak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Very recently, it has been found that organophosphorus nerve agents activate the endocannabinoid system inhibiting both enzymes FAAH and MAGL [9]. Arachidonic acid levels are decreased by the organophosphorus agents in amounts equivalent to elevations in 2-AG, which suggests that eicosanoid and endocannabinoid signalling pathways could co-ordinately regulated in the brain.…”

mentioning

confidence: 99%

Lipolytic enzymes as therapeutic targets

Kokotos

2008

Euro J Lipid Sci & Tech

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Editorial 1081 Editorial Lipolytic enzymes as therapeutic targetsLipids are essential components of the cell membrane that play a variety of dynamic roles in mediating and controlling a wide array of cellular activities including membrane structure and organization, metabolic and gene regulation, protein structure and function, energy storage and signaling pathways [1]. Lipolytic enzymes, i.e. the enzymes that catalyze the hydrolysis of lipids, play key roles in nearly all cells and organisms producing a variety of bioactive metabolites. Potent and selective inhibitors of lipolytic enzymes help to elucidate their physiological functions and associated metabolic pathways. Here, I would like to focus the attention on two lipolytic enzymes of high medicinal interest, namely phospholipase A 2 (PLA 2 ) and monoacylglycerol lipase (MAGL). Phospholipase A 2 enzymes catalyze the hydrolysis of the ester bond at the sn-2 position of glycerophospholipids releasing free fatty acids, including arachidonic acid, and lysophospholipids. Arachidonic acid and its various eicosanoid metabolites are critical second messengers in inflammation, pain, and many pathophysiological processes, while lysophospholipids is reported to form PAF, another important second messenger in inflammation, as well as other pathophysiological processes. The PLA 2 superfamily currently consists of fifteen groups and many subgroups of which a number of enzymes differ in primary sequence, structure and catalytic mechanism [2]. The three predominant types of phospholipase A 2 (PLA 2 ) found in human tissues are the cytosolic (such as the GIVA cPLA 2 ), the secreted (such as the GIVA sPLA 2 ), and the calcium-independent (such as the GVIA iPLA 2 ) enzymes. Although these enzymes display common enzymatic activities, each PLA 2 plays distinct roles in the molecular signaling and metabolism of phospholipids. Therefore, the development of selective inhibitors for individual PLA 2 enzymes is necessary in order to target PLA 2 -specific signaling pathways; however this is challenging due to the observed promiscuity of known PLA 2 inhibitors.The research on low molecular weight inhibitors of PLA 2 started more than fifteen years ago. At that time the interest was focused on secreted PLA 2 . Eli Lilly discovered a potent and selective inhibitor of sPLA 2 which entered clinical trials for the treatment of severe sepsis.

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Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

Silva

2020

Birth Defects Research

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Objectives Exposure to chlorpyrifos (CPF), a neurotoxic insecticide, is implicated with adverse neurodevelopmental effects in children through noncholinergic mechanisms. Methods This review presents qualitative and quantitative evidence in three animal models (rodent, zebrafish, and Caenorhabditis elegans), for neurodevelopmental and behavioral effects occurring at CPF doses lower than those inhibiting acetylcholinesterase (AChE). Results CPF treatment in rodents at low noncholinergic doses during neurodevelopment showed behavioral effects, including locomotor activity, neuromotor function (NMF), cognition, anxiety, social behavior, and maternal care. Zebrafish and C. elegans, which are transparent during development, allow for detailed analysis of specific systems; further, they exhibit neurotoxic effects closely emulating those observed in mammalian pathways. Qualitative results showed concordance among rodents, zebrafish and C. elegans for adverse effects on locomotor activity, NMF, and AChE inhibition. Male rodents had greater sensitivity for effects on locomotor activity than females and exposure during the gestation day 10–14 window showed consistent increases in locomotor activity at low CPF doses (≤1.0 mg kg−1 day−1). Zebrafish had cognitive and anxiety deficits after CPF treatment at low doses and young adult C. elegans had reproductive dysfunction associated NMF and disruption of the serotonergic pathway. Quantitative data for all three species showed neurobehavioral effects after exposure to CPF doses approximately 2–10‐fold below the threshold for AChE inhibition. Conclusions Taken together, these findings provided a weight‐of‐evidence for low‐dose CPF neurotoxicity and noncholinergic mechanisms. Variability in laboratories, exposure methods, tests, sex, and animal species/strain might have contributed to the inconsistent results. The detrimental CPF effects during early development are relevant to human populations.

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Activation of the endocannabinoid system by organophosphorus nerve agents

Cited by 109 publications

References 41 publications

Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins

Lipolytic enzymes as therapeutic targets

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

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