2AG is a major endocannabinoid produced from lipids in cellular membranes, mostly but not exclusively in response to cellular activity. In the brain, Endocannabinoids serve mainly as negative feedback molecules (reducing presynaptic neurotransmitter release after postsynaptic activation) keeping overall brain activity in balance. Throughout the body, Endocannabinoids are involved in the regulation of key processes such as cell division, energy metabolism, and inflammation. Therapeutically, 2AG has been associated with pain relief, suppression of vomiting and stimulation of appetite and the inhibition of tumor growth.
Chemical Name: 
2-Arachidonoyl glycerol
IUPHAR entry: 
Wikipedia entry: 
Synthetic Pathways: 

PLCβ: Phospholipase C β

Produces Diacylglycerol (DAG) from phospholipids

DAGLα: Diacylglycerol Lipase α

Produces 2AG from DAG

DAGLβ: Diacylglycerol Lipase β

Produces 2AG from DAG (probably not involved in depolarisation-induced suppression of excitation/inhibition (DSE/DSI))

Literature: Endocannabinoids, Related Compounds and Their Metabolic Routes. Fezza F, Bari M, Florio R, Talamonti E, Feole M, Maccarrone M. Molecules. 2014 Oct 24;19(11):17078-17106. Review. PMID: 25347455 Free Article

Degradation Pathways: 

Main pathway:

MAGL: Monoacylglycerol Lipase

 Serine hydrolase cleaving 2AG into arachidonic acid (AA) and glycerol

Additional pathways:

FAAH1: Fatty Acid Amide Hydrolase

Serine Hydrolase, probably more involved in Anandamide degradation

ABHD6: α/β Hydrolase

Serine Hydrolase, distribution in CNS distinct from MAGL and ABHD12, suggesting different physiological function

ABHD12: α/β Hydrolase

Serine Hydrolase, distribution in CNS distinct from MAGL and ABHD6, suggesting different physiological function

LOXx: Lipooxygenase

Degrades 2AG to 12-hydroxyarachidonoyl-glycerol (12-HETE-G)

COX-2: Cyclooxygenase-2

Degrades 2AG to prostaglandinglycerol E2-G (PGE2-G)

Literature: Endocannabinoids, Related Compounds and Their Metabolic Routes. Fezza F, Bari M, Florio R, Talamonti E, Feole M, Maccarrone M. Molecules. 2014 Oct 24;19(11):17078-17106. Review. PMID: 25347455 Free Article

Distribution: 

Relatively abundant in brain (compared to Anandamide), also found in breast milk.

Image: 
Receptors: 
Category: 
Literature Discussion: 

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). CB1 is not involved in plaque clearance.

Alzheimer’s patients have higher serum levels of 2AG and PEA. In these patients, 2AG is positively correlated with cognitive performance suggesting therapeutic potential. PEA was inversely correlated with cognitive performance, underlining the differential characteristics of cannabinoids (Altamura et al., 2015).

Anorexia

2AG and AEA are involved in food intake regulation (Fride, Bregman, & Kirkham, 2005)

cancer

Bladder Cancer

2AG regulates inflammation and proliferation processes of bladder carcinoma cells, probably through CB receptors (Gasperi et al., 2014).  

Depression

Anandamide levels (and to a lesser degree 2AG levels) and CB1 receptor availability are increased in the hippocampus (but not in the prefrontal cortex). Blocking the endocannabinoid system prevents the production of new neurons suggesting a role for cannabinoids in this process (Hill et al., 2010).

Eczema

In a mouse study, experimental dermatitis increased 2AG levels and suppressed inflammation via CB2 receptors (Oka et al., 2006).

Epilepsy

Neuronal activity induces a Cl- influx through 2AG/Anandamide and CB2 (den Boon et al., 2014).

Functional Gastro-Intestinal Disorders

Intracerebrovascular application of Anandamide and 2AG appeared gastro-protective in ethanol-induced ulcers suggesting the involvement of endocannabinoids in the central nervous system (Gyires and Zádori, 2016). In patients with diarrhea-type IBS higher levels of 2AG and lower levels of OEA and PEA were found. In contrast, patients with constipation-type IBS had higher levels of OEA and lower levels of FAAH. Also, PEA levels were inversely correlated with abdominal pain suggesting substantial involvement of the endocannabinoid system in the pathophysiology of IBS (Fichna et al., 2013).

References:

Altamura, C., Ventriglia, M., Martini, M.G., Montesano, D., Errante, Y., Piscitelli, F., Scrascia, F., Quattrocchi, C., Palazzo, P., Seccia, S., et al. (2015). Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer’s Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline. J. Alzheimers Dis. JAD.

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

den Boon, F.S., Chameau, P., Houthuijs, K., Bolijn, S., Mastrangelo, N., Kruse, C.G., Maccarrone, M., Wadman, W.J., and Werkman, T.R. (2014). endocannabinoids produced upon action potential firing evoke a Cl(-) current via type-2 cannabinoid receptors in the medial prefrontal cortex. Pflüg. Arch. Eur. J. Physiol. 466, 2257–2268.

Fichna, J., Sałaga, M., Stuart, J., Saur, D., Sobczak, M., Zatorski, H., Timmermans, J.-P., Bradshaw, H.B., Ahn, K., and Storr, M.A. (2014). Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 470–481.

Fride, E., Bregman, T., & Kirkham, T. C. (2005). Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Experimental Biology and Medicine (Maywood, N.J.)230(4), 225-234.

Gasperi, V., Evangelista, D., Oddi, S., Florenzano, F., Chiurchiù, V., Avigliano, L., Catani, M.V., and Maccarrone, M. (2014). Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. Life Sci.

Gyires, K., and Zádori, Z.S. (2016). Role of cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr. Neuropharmacol. 14, 935–951.

Hill, M.N., Titterness, A.K., Morrish, A.C., Carrier, E.J., Lee, T.T.-Y., Gil-Mohapel, J., Gorzalka, B.B., Hillard, C.J., and Christie, B.R. (2010). Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20, 513–523.

Oka, S., Wakui, J., Ikeda, S., Yanagimoto, S., Kishimoto, S., Gokoh, M., Nasui, M., and Sugiura, T. (2006). Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice. J. Immunol. Baltim. Md 1950 177, 8796–8805.