“The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28434588]]>
Tag Archives: endocannabinoid system
Endocannabinoid system acts as a regulator of immune homeostasis in the gut
“Exogenous cannabinoids such as marijuana exert their influence through cannabinoid receptors. Endogenous cannabinoids such as anandamide (AEA) function through the same receptors, and their physiological roles are a subject of intense study. Here, we show that AEA plays a pivotal role in maintaining immunological health in the gut. The immune system in the gut actively tolerates the foreign antigens present in the gut through mechanisms that are only partially understood. We show that AEA contributes to this critical process by promoting the presence of CX3CR1hi macrophages, which are immunosuppressive. These results uncover a major conversation between the immune and nervous systems. In addition, with the increasing prevalence of ingestion of exogenous marijuana, our study has significant implications for public health.” http://www.pnas.org/content/early/2017/04/18/1612177114.full “Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.” https://www.ncbi.nlm.nih.gov/pubmed/28439004
“Active ingredients in both hot peppers and cannabis calm the gut’s immune system” https://medicalxpress.com/news/2017-04-ingredients-hot-peppers-cannabis-calm.html
]]>Editorial: The CB2 Cannabinoid System: A New Strategy in Neurodegenerative Disorder and Neuroinflammation
“The cannabinoid receptors subtype 2 (CB2R) are emerging as novel targets for the development of new therapeutic approaches and PET probes useful to early diagnose neuroinflammation as first step in several neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson disease (PD).
This Research Topic is mainly focused on the involvment of CB2R in neurodegenerative disorders and on the usefulness of CB2R ligands in the therapy and early diagnosis of neuroinflammation as onset of neurodegeneration.
In the reviews of Aso and Ferrer and Cassano et al. an interesting and exaustive overview of the endogenous cannabinoid signaling and its role in neuroinflammation and neurogenesis is reported. The potential of CB2R as therapeutic target in AD is argued by several evidences derived by robust experimental models and the effects modulated by CB2R agonists on different pathways involved in the pathogenesis of AD are discussed; indeed, these ligands are able to reduce inflammation, Aβ production and deposition, tau protein hyper-phosphorylation and oxidative stress damage caused by Aβ peptides. CB2R agonists are also able to induce Aβ clearance leading to cognitive improvement in AD models.
In conclusion, considering that neuroinflammation has been widely reported as indicator and modulator of neurodegeneration, the reduction of the neuroinflammatory responses could be considered as a new therapeutic strategy in these diseases. Moreover, the selective CB2R overexpression on the activated-microglial cells provides also a highly specialized target useful to an early diagnosis of the neurodegenerative diseases.”
http://journal.frontiersin.org/article/10.3389/fnins.2017.00196/full]]>Anandamide and 2-AG Are Endogenously Present within the Laterodorsal Tegmental Nucleus: Functional Implications for a role of eCBs in arousal.
“Previously, we presented electrophysiological evidence for presence in mice brain slices of functional cannabinoid type I receptors (CB1Rs) within the laterodorsal tegmentum (LDT), a brain stem nucleus critical in control of arousal and rapid eye movement (REM) sleep. Further, using pharmacological agents, we provided data suggestive of the endogenous presence of cannabinoids (CBs) acting at LDT CB1Rs. However, in those studies, we were unable to identify the type(s) of CB ligands endogenously present in the LDT, and this information has not been provided elsewhere. Accordingly, we used the highly-sensitive liquid chromatography/mass spectrometry (LC-MS) method to determine whether N-arachidonoylethanolamide (Anandamide or AEA) and 2-arachidonyl glycerol (2-AG), which are both endogenous CB ligands acting at CB1Rs, are present in the LDT. Mice brain tissue samples of the LDT were assayed using ion trap LC-MS in selected ion monitoring mode. Chromatographic analysis and product-ion MS scans identified presence of the CBs, AEA and 2-AG, from LDT mouse tissue. Data using the LC-MS method show that AEA and 2-AG are endogenously present within the LDT and when coupled with our electrophysiological findings, lead to the suggestion that AEA and 2-AG act at electropharmacologically-demonstrated CB1Rs in this nucleus. Accordingly, AEA and 2-AG likely play a role in processes governed by the LDT, including control of states of cortical gamma band activity seen in alert, aroused states, as well as cortical and motor activity characteristic of REM sleep.” https://www.ncbi.nlm.nih.gov/pubmed/28404451]]>
Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment
“We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).
Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.
The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.
In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome
“Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain.
The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.” http://www.nature.com/articles/ncomms2045
“Cannabis-like chemical combats chief genetic cause of autism” http://www.belfasttelegraph.co.uk/news/health/cannabislike-chemical-combats-chief-genetic-cause-of-autism-28867862.html#ixzz2DRLsbjJO
Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.
“The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a ‘peripherally’ restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN.
RESULTS.:
Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells.CONCLUSION.:
‘Peripheral’ CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.” https://www.ncbi.nlm.nih.gov/pubmed/28387811]]>Metabolic Syndrome Induced Bladder Cannabinoid Receptor Changes in the Fructose-Fed Rats.
“To investigate the effect of metabolic syndrome on the bladder cannabinoid receptors 1 and 2 (CB1/CB2) expression and function in the fructose-fed rats (FR).
CONCLUSION:
CB1/CB2 receptors mediate rat bladder relaxation through the PKA and KATP pathway. The CB1 receptor may play a more prominent role. The response is decreased in the FR bladder due to reduced expressions of the cannabinoid receptors.” https://www.ncbi.nlm.nih.gov/pubmed/28386998]]>Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.
“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.”
https://www.ncbi.nlm.nih.gov/pubmed/28380440