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, pain, Anxiety, 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:
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