MAGL accounts for 85% of 2-AG degradation in the brain.

Chemical Name: 
Monoacylglycerol Lipase
Therapeutic Indication: 

MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases as Alzheimers, ischemic injuries, inflammation, pain, Anxiety, nausea and drug-withdrawal symptoms (Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013) 

Wikipedia entry: 
Receptors: 
Endocannabinoids: 
Literature Discussion: 

MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, pain, Anxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013) 

endocannabinoid system interactions

Monoacylglycerol lipase degrades 2-AG and colocalizes with CB1 receptors in the brain (Savinainen, Saario, & Laitinen, 2012)

MAGL is expressed in neurons and in astrocytes with different functions in each type of cell. It works as a high 2-AG hydrolyser when is expressed in the former and it converts 2-AG to prostaglandins when is expressed in the latter (Viader et al., 2015)

MAGL, as well as the synthesizing enzyme DAGLα, are involved in the development of the retina from early postnatal development until adulthood (Cécyre, Monette, Beudjekian, Casanova, & Bouchard, 2014)

MAGL is overexpressed in human cancer cells, modulates tumor growth and could be a prognostic indicator for Hepatocellular Carcinoma (Nomura et al., 2010; Zhang et al., 2016; Zhu et al., 2016)

Overexpression of MAGL in glutamatergic neurons of the mouse hippocampus decreased 2-AG levels impairing depolarization-induced suppression of excitation with Anxiety-like behavior linked to it (Guggenhuber et al., 2015)

Inhibition of MAGL increases 2-AG in the brain and downregulates CB1 receptor expression affecting long-term synaptic plasticity and learning behavior (Griebel et al., 2015; Liu et al., 2016; Pan et al., 2011; Zhong et al., 2011)

MAGL inhibition counteracts insulin resistance without impairing food intake behavior in animals (Taschler et al., 2011)

In contrast to FHHA inhibition, prolonged MAGL inhibition reduces or deletes its analgesic properties causing tolerance and CB1 receptor desensitization (Schlosburg et al., 2010)

Alzheimer´s

One therapeutic indication for CB2 is the stimulation of Amyloid β plaque removal by macrophages. Similar effects were seen for 2AG and MAGL inhibitors (Chen et al., 2012).

pain

MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, painAnxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013) 

Pancreatic cancer

In human patients, high CB1 expression in pancreatic cancer cells was associated with reduced survival. Similarly, low levels of endocannabinoid-degrading enzyme FAAH and MAGL were associated with reduced survival. Interestingly, Anandamide and 2AG levels were unchanged in pancreatic cancer. Finally, contrary to CB1 expression in cancer cells, low CB1 in nervous tissue was associated with increased cancer pain, but also increased survival (Michalski et al., 2008). The mechanistic value of these correlations remains to be elucidated

psychosis and schizophrenia

DAGL and NAPE are downregulated while MAGL and FAAH are upregulated in subjects who had a first episode of psychosis (Bioque et al., 2013).

References:

Bioque, M., García-Bueno, B., Macdowell, K. S., Meseguer, A., Saiz, P. A., Parellada, M., … FLAMM-PEPs study—Centro de Investigacio´n Biome´dica en Red de Salud Mental. (2013). Peripheral endocannabinoid system dysregulation in first-episode Psychosis. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38(13), 2568-2577. https://doi.org/10.1038/npp.2013.165

Cécyre, B., Monette, M., Beudjekian, L., Casanova, C., & Bouchard, J.-F. (2014). Localization of diacylglycerol lipase alpha and monoacylglycerol lipase during postnatal development of the rat retina. Frontiers in Neuroanatomy, 8. https://doi.org/10.3389/fnana.2014.00150

Chen, R., Zhang, J., Wu, Y., Wang, D., Feng, G., Tang, Y.-P., … Chen, C. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports, 2(5), 1329-1339. https://doi.org/10.1016/j.celrep.2012.09.030

Griebel, G., Pichat, P., Beeské, S., Leroy, T., Redon, N., Jacquet, A., … Escoubet, J. (2015). Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents. Scientific Reports, 5. https://doi.org/10.1038/srep07642

Guggenhuber, S., Romo-Parra, H., Bindila, L., Leschik, J., Lomazzo, E., Remmers, F., … Lutz, B. (2015). Impaired 2-AG Signaling in Hippocampal Glutamatergic Neurons: Aggravation of Anxiety-Like Behavior and Unaltered Seizure Susceptibility. International Journal of Neuropsychopharmacology, 19(2). https://doi.org/10.1093/ijnp/pyv091

Kohnz, R., & Nomura, D. K. (2014). Chemical Approaches to Therapeutically Target the Metabolism and Signaling of the endocannabinoid 2-AG and Eicosanoids. Chemical Society reviews, 43(19), 6859-6869. https://doi.org/10.1039/c4cs00047a

Liu, X., Chen, Y., Vickstrom, C. R., Li, Y., Viader, A., Cravatt, B. F., & Liu, Q. (2016). Coordinated regulation of endocannabinoid-mediated retrograde synaptic suppression in the cerebellum by neuronal and astrocytic monoacylglycerol lipase. Scientific Reports, 6. https://doi.org/10.1038/srep35829

Michalski, C.W., Oti, F.E., Erkan, M., Sauliunaite, D., Bergmann, F., Pacher, P., Batkai, S., Müller, M.W., Giese, N.A., Friess, H., et al. (2008). cannabinoids in pancreatic cancer: correlation with survival and pain. Int. J. cancer 122, 742–750.

Mulvihill, M. M., & Nomura, D. K. (2013). Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life sciences, 92(8-9), 492-497. https://doi.org/10.1016/j.lfs.2012.10.025

Nomura, D. K., Long, J. Z., Niessen, S., Hoover, H. S., Ng, S.-W., & Cravatt, B. F. (2010). Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell, 140(1), 49-61. https://doi.org/10.1016/j.cell.2009.11.027

Pan, B., Wang, W., Zhong, P., Blankman, J. L., Cravatt, B. F., & Liu, Q. (2011). Alterations of endocannabinoid signaling, synaptic plasticity, learning and memory in monoacylglycerol lipase knockout mice. The Journal of Neuroscience, 31(38), 13420-13430. https://doi.org/10.1523/JNEUROSCI.2075-11.2011

Savinainen, J. R., Saario, S. M., & Laitinen, J. T. (2012). The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiologica (Oxford, England), 204(2), 267-276. https://doi.org/10.1111/j.1748-1716.2011.02280.x

Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., … Cravatt, B. F. (2010). Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nature Neuroscience, 13(9), 1113-1119. https://doi.org/10.1038/nn.2616

Taschler, U., Radner, F. P. W., Heier, C., Schreiber, R., Schweiger, M., Schoiswohl, G., … Zimmermann, R. (2011). Monoglyceride Lipase Deficiency in Mice Impairs Lipolysis and Attenuates Diet-induced Insulin Resistance. The Journal of Biological Chemistry, 286(20), 17467-17477. https://doi.org/10.1074/jbc.M110.215434

Viader, A., Blankman, J. L., Zhong, P., Liu, X., Schlosburg, J. E., Joslyn, C. M., … Cravatt, B. F. (2015). Metabolic Interplay between Astrocytes and Neurons Regulates endocannabinoid Action. Cell reports, 12(5), 798-808. https://doi.org/10.1016/j.celrep.2015.06.075

Zhang, J., Liu, Z., Lian, Z., Liao, R., Chen, Y., Qin, Y., … Gong, J. (2016). Monoacylglycerol Lipase: A Novel Potential Therapeutic Target and Prognostic Indicator for Hepatocellular Carcinoma. Scientific Reports, 6. https://doi.org/10.1038/srep35784

Zhong, P., Pan, B., Gao, X., Blankman, J. L., Cravatt, B. F., & Liu, Q. (2011). Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum. The Journal of Physiology, 589(Pt 20), 4847-4855. https://doi.org/10.1113/jphysiol.2011.215509

Zhu, W., Zhao, Y., Zhou, J., Wang, X., Pan, Q., Zhang, N., … Wang, L. (2016). Monoacylglycerol lipase promotes progression of hepatocellular carcinoma via NF-κB-mediated epithelial-mesenchymal transition. Journal of Hematology & Oncology, 9. https://doi.org/10.1186/s13045-016-0361-3

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