DAGL is responsible for the biosynthesis of 2-AG (Biernacki & Skrzydlewska, 2016).
Zebrafish DAGLα knockdown experiments showed that 2-AG modulates axon formation in the midbrain and hindbrain areas, suggesting its implication in the control of vision and movement (Martella et al., 2016).
Inhibition of DAGL reduced the movement of neuroblasts in the rostral migratory steam and when these were moving, they moved in random directions. This effect was mediated by 2-AG and CB1 receptors and has important implications for the understanding of CNS development (Oudin, Gajendra, et al., 2011; Zhou et al., 2015).
DAGL modulates brain lipid transmitters like endocannabinoids, eicosanoids and diacylglycerols. This lipid signaling modulates synaptic plasticity, neuroinflammation and behaviors related to pain, emotions and addictions (Ogasawara et al., 2016). Inhibition of DAGL reduces 2-AG levels as well as synaptic plasticity in the hippocampus of mice, suggesting that on-demand 2-AG biosynthesis modulates retrograde signaling (Baggelaar et al., 2015). DAGL has been associated with synaptic plasticity and retrograde signaling in several studies (Gao et al., 2010; Marinelli et al., 2008; Oudin, Hobbs, & Doherty, 2011; Yoshino et al., 2011).
Addiction
Nicotine exposure in rats increased 2-AG biosynthesis in the ventral tegmental area (VTA). 2-AG reduces GABA signaling, increasing VTA sensitivity to nicotine and increasing sensitization of DA release in the nucleus accumbens. Inhibition of DAGL restored GABA signaling in the VTA, making DAGL an interesting target to treat addictions (Buczynski et al., 2016). Following the same line, Morphine withdrawal increased DAGLα expression in rat nucleus accumbens and increased depolarization-induced suppression of inhibition, suggesting that 2-AG mediates this process (Wang et al., 2016). Furthermore, a study testing the effects of cocaine in orexin neurons found very similar results (Tung et al., 2016).
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)
anxiety
DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and anxiety responses (Jenniches et al., 2016).
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). DAGLα is expressed in the enteric nervous system including the gastrointestinal tract. Genetically constipated mice and CB1 deficient mice reversed their symptoms of slow gastrointestinal motility, intestinal contractility and constipation after DAGLα inhibition. These effects were mediated by 2-AG and CB1 receptors (Bashashati et al., 2015).
Hypoxic-Ischemic Encephalopaty
cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England et al., 2015; Lara-Celador et al., 2013).
insomnia
The administration of 2-AG restores sleep in the same model of maternal separation but not in wild type rats, proving the role of the endocannabinoid system in sleep processes (Pérez-Morales et al., 2014).
Metabolic disorders, Eating disorders and obesity
endocannabinoids are derived from Poly Unsaturated Fatty Acids (PUFAs) with Anandamide and 2AG coming from Ω-6 PUFAs and EPA and DHA coming from Ω-3 PUFAs. The typical Western diet is low on PUFAs and has a low Ω-3/Ω-6 ratio. Shifting the balance to a higher Ω-3 content leads to weight loss, presumably through differential activation of the endocannabinoidsystem (Watkins and Kim, 2014). DAGL inhibitors have been proposed to treat metabolic disorders due to their effects on the CB1 receptor through 2-AG (Janssen & van der Stelt, 2016). DAGL inhibitors can avoid fasting-induced refeeding of mice, showing a similar pharmacokinetic profile to CB1 inverse agonists (Deng et al., 2017). There are other studies linking DAGL and 2-AG activity with eating disorders (Bisogno et al., 2013; Engeli et al., 2014). Also, DAGL inhibition reverts the effects on food intake and rapid eye movement sleep in rats caused by the stimulation protease activated receptor 1 (PPAR-1) in the lateral hypothalamus. This suggest synergistic actions between PAR1 and 2-AG (Pérez-Morales, Fajardo-Valdez, Méndez-Díaz, Ruiz-Contreras, & Prospéro-García, 2014).
pain
Nox-induced oxyradical stress elicited the activation of DAGLβ in vitro, increasing the biosynthesis of 2-AG (Matthews et al., 2016). DAGLβ modulates pro-inflammatory signaling cascades and its inhibition reduced nociceptive behavior in models of neuropathic and inflammatory pain (Wilkerson et al., 2016).
Parkinson´s
Similar results were obtained with 2AG, the body’s major endocannabinoid (Mounsey et al., 2015).
psychosis and schizophrenia
Regarding the molecular mechanisms of the comorbidity between cannabis and schizophrenia, the endocannabinoid system has been related to schizophrenia. endocannabinoids like Anandamide and 2-AG play an important role on psychosis (Manseau and Goff, 2015).
Tinnitus
CB1 receptors and 2AG are expressed in the auditory brainsteam and their role may involve modulation of the balance of excitation and inhibition in auditory circuits (Zhao et al., 2009)
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.
Baggelaar, M. P., Chameau, P. J. P., Kantae, V., Hummel, J., Hsu, K.-L., Janssen, F., … van der Stelt, M. (2015). Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. Journal of the American Chemical Society, 137(27), 8851-8857. https://doi.org/10.1021/jacs.5b04883
Bashashati, M., Nasser, Y., Keenan, C. M., Ho, W., Piscitelli, F., Nalli, M., … Sharkey, K. A. (2015). Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. British Journal of Pharmacology, 172(12), 3099-3111. https://doi.org/10.1111/bph.13114
Biernacki, M., & Skrzydlewska, E. (2016). Metabolism of endocannabinoids. Postepy Higieny I Medycyny Doswiadczalnej (Online), 70(0), 830-843.
Bisogno, T., Mahadevan, A., Coccurello, R., Chang, J. W., Allarà, M., Chen, Y., … Di Marzo, V. (2013). A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects. British Journal of Pharmacology, 169(4), 784-793. https://doi.org/10.1111/bph.12013
Buczynski, M. W., Herman, M. A., Hsu, K.-L., Natividad, L. A., Irimia, C., Polis, I. Y., … Parsons, L. H. (2016). Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proceedings of the National Academy of Sciences of the United States of America, 113(4), 1086-1091. https://doi.org/10.1073/pnas.1522672113
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.
Deng, H., Kooijman, S., van den Nieuwendijk, A. M. C. H., Ogasawara, D., van der Wel, T., van Dalen, F., … van der Stelt, M. (2017). Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding. Journal of Medicinal Chemistry, 60(1), 428-440. https://doi.org/10.1021/acs.jmedchem.6b01482
Engeli, S., Lehmann, A.-C., Kaminski, J., Haas, V., Janke, J., Zoerner, A. A., … Jordan, J. (2014). Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. obesity, 22(5), E70-E76. https://doi.org/10.1002/oby.20728
England, T.J., Hind, W.H., Rasid, N.A., and O’Sullivan, S.E. (2015). cannabinoids in experimental stroke: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 35, 348–358.
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.
Gao, Y., Vasilyev, D. V., Goncalves, M. B., Howell, F. V., Hobbs, C., Reisenberg, M., … Doherty, P. (2010). Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(6), 2017-2024. https://doi.org/10.1523/JNEUROSCI.5693-09.2010
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.
Janssen, F. J., & van der Stelt, M. (2016). Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders. Bioorganic & Medicinal Chemistry Letters, 26(16), 3831-3837. https://doi.org/10.1016/j.bmcl.2016.06.076
Jenniches, I., Ternes, S., Albayram, O., Otte, D. M., Bach, K., Bindila, L., … Zimmer, A. (2016). anxiety, Stress, and Fear Response in Mice With Reduced endocannabinoid Levels. Biological Psychiatry, 79(10), 858-868. https://doi.org/10.1016/j.biopsych.2015.03.033
Lara-Celador, I., Goñi-de-Cerio, F., Alvarez, A., and Hilario, E. (2013). Using the endocannabinoid system as a neuroprotective strategy in perinatal hypoxic-ischemic brain injury. Neural Regen. Res. 8, 731–744
Manseau, M.W., and Goff, D.C. (2015). cannabinoids and schizophrenia: Risks and Therapeutic Potential. Neurotherapeutics 1–9
Marinelli, S., Pacioni, S., Bisogno, T., Di Marzo, V., Prince, D. A., Huguenard, J. R., & Bacci, A. (2008). The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical interneurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(50), 13532-13541. https://doi.org/10.1523/JNEUROSCI.0847-08.2008
Martella, A., Sepe, R. M., Silvestri, C., Zang, J., Fasano, G., Carnevali, O., … Marzo, V. D. (2016). Important role of endocannabinoid signaling in the development of functional vision and locomotion in zebrafish. The FASEB Journal, 30(12), 4275-4288. https://doi.org/10.1096/fj.201600602R
Matthews, A. T., Lee, J. H., Borazjani, A., Mangum, L. C., Hou, X., & Ross, M. K. (2016). Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase. American Journal of Physiology - Cell Physiology, 311(6), C960-C974. https://doi.org/10.1152/ajpcell.00251.2015
Mounsey, R.B., Mustafa, S., Robinson, L., Ross, R.A., Riedel, G., Pertwee, R.G., and Teismann, P. (2015). Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Exp. Neurol.
Ogasawara, D., Deng, H., Viader, A., Baggelaar, M. P., Breman, A., den Dulk, H., … van der Stelt, M. (2016). Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proceedings of the National Academy of Sciences of the United States of America, 113(1), 26-33. https://doi.org/10.1073/pnas.1522364112
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.
Oudin, M. J., Gajendra, S., Williams, G., Hobbs, C., Lalli, G., & Doherty, P. (2011). endocannabinoids regulate the migration of subventricular zone-derived neuroblasts in the postnatal brain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(11), 4000-4011. https://doi.org/10.1523/JNEUROSCI.5483-10.2011
Oudin, M. J., Hobbs, C., & Doherty, P. (2011). DAGL-dependent endocannabinoid signalling: roles in axonal pathfinding, synaptic plasticity and adult neurogenesis. European Journal of Neuroscience, 34(10), 1634-1646. https://doi.org/10.1111/j.1460-9568.2011.07831.x
Pérez-Morales, M., Fajardo-Valdez, A., Méndez-Díaz, M., Ruiz-Contreras, A.E., and Prospéro-García, O. (2014). 2-Arachidonoylglycerol into the lateral hypothalamus improves reduced sleep in adult rats subjected to maternal separation. Neuroreport 25, 1437–1441.
Tung, L.-W., Lu, G.-L., Lee, Y.-H., Yu, L., Lee, H.-J., Leishman, E., … Chiou, L.-C. (2016). Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nature Communications, 7, 12199. https://doi.org/10.1038/ncomms12199
Wang, X.-Q., Ma, J., Cui, W., Yuan, W.-X., Zhu, G., Yang, Q., … Gao, G.-D. (2016). The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL-α expression following short-term morphine withdrawal. British Journal of Pharmacology, 173(7), 1143-1153. https://doi.org/10.1111/bph.12969
Watkins, B.A., and Kim, J. (2014). The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front. Psychol. 5, 1506.
Wilkerson, J. L., Ghosh, S., Bagdas, D., Mason, B. L., Crowe, M. S., Hsu, K. L., … Lichtman, A. H. (2016). Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. British Journal of Pharmacology, 173(10), 1678-1692. https://doi.org/10.1111/bph.13469
Yoshino, H., Miyamae, T., Hansen, G., Zambrowicz, B., Flynn, M., Pedicord, D., … Gonzalez-Burgos, G. (2011). Postsynaptic diacylglycerol lipase mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex. The Journal of Physiology, 589(Pt 20), 4857-4884. https://doi.org/10.1113/jphysiol.2011.212225
Zhao, Y., Rubio, M.E., and Tzounopoulos, T. (2009). Distinct functional and anatomical architecture of the endocannabinoid system in the auditory brainstem. J. Neurophysiol. 101, 2434–2446.
Zhou, Y., Oudin, M. J., Gajendra, S., Sonego, M., Falenta, K., Williams, G., … Doherty, P. (2015). Regional effects of endocannabinoid, BDNF and FGF receptor signalling on neuroblast motility and guidance along the rostral migratory stream. Molecular and Cellular Neurosciences, 64, 32-43. https://doi.org/10.1016/j.mcn.2014.12.001
