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).
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).
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).
2AG and AEA are involved in food intake regulation (Fride, Bregman, & Kirkham, 2005)
DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and Anxiety responses (Jenniches et al., 2016).
2AG regulates inflammation and proliferation processes of bladder carcinoma cells, probably through CB receptors (Gasperi et al., 2014).
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).
In a mouse study, experimental dermatitis increased 2AG levels and suppressed inflammation via CB2 receptors (Oka et al., 2006).
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).
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).
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).
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).
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).
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)
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