Therapeutic potential of monoacylglycerol lipase inhibitors.
Source
Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
Abstract
Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulatingcannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown beneficial outcomes in mouse models of neurodegenerative diseases andcancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases.
Copyright © 2012 Elsevier Inc. All rights reserved.
Copyright © 2012 Elsevier Inc. All rights reserved.
- PMID:
- 23142242
- [PubMed – indexed for MEDLINE]
- PMCID:
- PMC3594462
- [Available on 2014/3/19]
Publication Types, MeSH Terms, Substances, Grant Support
Publication Types
MeSH Terms
- Animals
- Anxiety/drug therapy
- Anxiety/enzymology
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use*
- Humans
- Inflammation/drug therapy
- Inflammation/enzymology
- Monoacylglycerol Lipases/antagonists & inhibitors*
- Monoacylglycerol Lipases/physiology
- Neoplasms/drug therapy
- Neoplasms/enzymology
- Pain/enzymology
- Substance-Related Disorders/drug therapy
- Substance-Related Disorders/enzymology
Substances
Grant Support
LinkOut – more resources
Full Text Sources
Education
Figures and tables from this article:
- Fig. 1. MAGL coordinately regulates multiple lipid signaling pathways. MAGL blockade leads to an accumulation of the endocannabinoid 2-AG to enhance signaling upon cannabinoid receptors CB1 and CB2. In certain tissues, such as the brain, liver, and lung, MAGL controls the primary AA precursor pool for pro-inflammatory prostaglandin production. Blocking MAGL thus leads to a variety of beneficial effects through either enhancing endocannabinoid signaling or suppressing eicosanoid production. In cancer, MAGL plays a distinct role in controlling global FFAs levels that serve as the building blocks for synthesis of pro-tumorigenic signaling lipids such as PGE2 and lysophosphatidic acid (LPA). Blocking MAGL in aggressive cancer cells leads to a reduction in FFAs and attenuated cancer cell pathogenicity.
- Corresponding author. Tel.: + 1 510 643 7258.
Copyright © 2012 Elsevier Inc. All rights reserved.
Figures and tables from this article:
- Fig. 1. MAGL coordinately regulates multiple lipid signaling pathways. MAGL blockade leads to an accumulation of the endocannabinoid 2-AG to enhance signaling upon cannabinoid receptors CB1 and CB2. In certain tissues, such as the brain, liver, and lung, MAGL controls the primary AA precursor pool for pro-inflammatory prostaglandin production. Blocking MAGL thus leads to a variety of beneficial effects through either enhancing endocannabinoid signaling or suppressing eicosanoid production. In cancer, MAGL plays a distinct role in controlling global FFAs levels that serve as the building blocks for synthesis of pro-tumorigenic signaling lipids such as PGE2 and lysophosphatidic acid (LPA). Blocking MAGL in aggressive cancer cells leads to a reduction in FFAs and attenuated cancer cell pathogenicity.
- Corresponding author. Tel.: + 1 510 643 7258.
Copyright © 2012 Elsevier Inc. All rights reserved.
