A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-Arachidonoylglycerol

Blankman, Jacqueline L.; Simón, Gabriel; Cravatt, Benjamin F.

doi:10.1016/j.chembiol.2007.11.006

Cited by 1,021 publications

(1,118 citation statements)

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“…22 MAGL is the primary enzyme degrading 2-AG in the brain. 14,15 Previous studies demonstrated that MAGL inactivation suppresses inflammatory cytokines in response to proinflammatory insults and neurodegeneration in an MPTP model of Parkinson's disease. 21 Moreover, inhibition of 2-AG metabolism reduces Aβ production, gliosis, and neurodegeneration, and prevents deteriorations in synaptic plasticity and cognitive function in animal models of AD.…”

Section: Discussionmentioning

confidence: 99%

“…2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for both CB1/2 receptors, is primarily produced from diacylglycerol by diacylglycerol lipase (α and β) and largely hydrolyzed by monoacylglycerol lipase (MAGL) in the brain. 14,15 Earlier studies show that the levels of 2-AG are significantly increased in the brain following closed head injury (CHI) and that administration of 2-AG attenuates TBI-induced neuropathology, [16][17][18] indicating that 2-AG likely is an endogenous signaling mediator 'on demand' that maintains brain homeostasis against harmful insults. Indeed, 2-AG possesses significant anti-inflammatory and neuroprotective properties in response to proinflammatory, excitotoxic, and mechanic insults.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Zhang

Teng

Song

et al. 2015

J Cereb Blood Flow Metab

102

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Emerging evidence suggests that the risk of developing chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease, is significantly increased in military personnel and contact sports players who have been exposed to repetitive trauma brain injury (TBI). Unfortunately there are no effective medications currently available for prevention and treatment of CTE. Here we demonstrate that inhibition of monoacylglycerol lipase (MAGL), the key enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, significantly reduced CTE-like neuropathologic changes in a mouse model of repetitive mild closed head injury (rmCHI). Inhibition of 2-AG metabolism promoted neurologic recovery following rmCHI and reduced proinflammatory cytokines, astroglial reactivity, expression of amyloid precursor protein and the enzymes that make Aβ, as well as formation of Aβ. Importantly, neurodegeneration, TDP-43 protein aggregation, and tau phosphorylation, which are the neuropathologic hallmarks of CTE, were significantly suppressed by MAGL inactivation. Furthermore, alterations in expression of glutamate receptor subunits and impairments in basal synaptic transmission, long-term synaptic plasticity, and spatial learning and memory were recovered by inhibition of 2-AG metabolism in animals exposed to rmCHI. Our results suggest that MAGL inhibition, which boosts 2-AG and reduces 2-AG metabolites prostaglandins in the brain, may lead to a new therapy for CTE.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Zhang

Teng

Song

et al. 2015

J Cereb Blood Flow Metab

102

View full text Add to dashboard Cite

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“…2) was found to be a potent inhibitor of MGL, inhibiting 2-AG hydrolysis in rat cerebellar membranes with an IC 50 value of 140 nM [45], a result confirmed using human recombinant MGL (hrMGL), and 2-OG as substrate [46]. Despite containing a highly reactive maleimide group, NAM has been shown to exhibit rather high selectivity for MGL relative to other brain serine hydrolases [37]. Other approaches have also yielded compounds that inhibit MGL, but with potencies in the micromolar range [47].…”

Section: Introductionmentioning

confidence: 73%

“…However, the main enzyme responsible for the inactivation of 2-AG in the brain has been suggested to be MGL (EC 3.1.1.23) [9,33,37], although other hydrolytic activities may also contribute to the metabolism [34][35][36][37]. MGL is a serine hydrolase, which hydrolyzes medium-and long-chain fatty acid esters such as 2-AG and its analogue 2-oleoylglycerol (2-OG) [9,38].…”

Section: Introductionmentioning

confidence: 99%

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

Minkkilä

Myllymäki

Saario

et al. 2009

European Journal of Medicinal Chemistry

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“…AEA 1 is metabolized by fatty acid amide hydrolase (FAAH), whereas monoacylglycerol lipase (MAGL) is the major catabolic enzyme of 2-AG. 2 These endogenous cannabinoids as well as exogenously administered cannabinoids activate two cannabinoid receptors, CB 1 and CB 2 . 3,4 CB 1 receptors are heterogeneously distributed in high concentrations throughout the central nervous system and periphery and are the predominant target for the psychomimetic effects of Δ 9 -tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana.…”

mentioning

confidence: 99%

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

Wise

Long

Abdullah

et al. 2012

ACS Chem. Neurosci.

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Acute administration of Δ 9 -tetrahydrocannabinol (THC) or exposure to marijuana smoke impairs short-term spatial memory in water maze tasks through a CB 1 receptor mechanism of action. N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids that are predominantly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Although the MAGL inhibitor JZL184 enhances short-term synaptic plasticity, it has yet to be evaluated in the Morris water maze. Previous research demonstrated that simultaneous, complete blockade of FAAH and MAGL produces full blown THC-like effects. Thus, in the following studies we tested whether dual blockade of FAAH and MAGL would impair learning in a repeated acquisition Morris water maze task. Mice treated with the dual FAAH/MAGL inhibitor JZL195 (20 mg/kg) as well as JZL184-treated FAAH −/− mice displayed robust deficits in Morris water maze performance that were similar in magnitude to THC-treated mice. While 20 or 40 mg/kg impaired water maze performance in FAAH −/− mice, only the high dose of JZL184 disrupted performance in FAAH +/+ mice. The memory impairing effects of JZL184 were blocked by the CB 1 receptor antagonist rimonabant. Neither JZL184 nor JZL195 impaired performance in a cued version of the water maze task, arguing against the notion that sensorimotor or motivational deficits accounted for the impaired acquisition performance. JZL184 increased 2-AG levels in the hippocampus, prefrontal cortex, and cerebellum to a similar degree in FAAH −/− and +/+ mice. FAAH −/− mice, regardless of drug treatment, possessed elevated AEA levels in each brain region assessed. The results of this study reveal that concomitant increases in AEA and 2-AG disrupt short-term spatial memory performance in a manner similar to that of THC. KEYWORDS: Cannabinoid, memory, N-arachidonoylethanolamine (anandamide), 2-arachidonoylglycerol (2-AG), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL)The endogenous cannabinoid signaling system has been widely studied to understand its role in physiological and pathological processes. To date, two major endogenous cannabinoids, Narachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), and their distinct biosynthetic and degradative pathways have been extensively investigated. Both AEA and 2-AG are synthesized and released on demand, in response to diverse physiological stimuli, and are rapidly inactivated by hydrolysis after cellular reuptake. AEA 1 is metabolized by fatty acid amide hydrolase (FAAH), whereas monoacylglycerol lipase (MAGL) is the major catabolic enzyme of 2-AG. 2 These endogenous cannabinoids as well as exogenously administered cannabinoids activate two cannabinoid receptors, CB 1 and CB 2 . 3,4 CB 1 receptors are heterogeneously distributed in high concentrations throughout the central nervous system and periphery and are the predominant target for the psychomimetic effects of Δ 9 -tetrahydrocannabi...

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A Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-Arachidonoylglycerol

Cited by 1,021 publications

References 47 publications

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

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