Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acylethanolamides are endogenous compounds with lipid structure including anandamide (AEA), palmitoilethanolamide, oleylamide and oleylethanolamide (OEA). AEA binds to the cannabinoid receptor CB1, located at the central nervous system, while OEA is an endogenous ligand for the alpha subtype of peroxisome-proliferator activating receptor (PPARalpha). Since AEA acts on the same receptor which binds marihuana active derivatives, this group of compounds were called endocannabinoids. Besides typical central effects of cannabinoids, CB1 receptor activation leads to hyperphagia, whereas its pharmacological blockade is followed by changes in energy metabolism favouring substrate oxidation. OEA has inhibitory effects on food intake by acting on PPARalpha receptors which modulate the autonomous nervous system. Both acylethanolamides, AEA and OEA, have opposite effects suggesting that they form part of a satiety sensor system. Whereas fasting triggers AEA release and inhibits OEA synthesis, eating has the reverse effect. Additionally OEA is also produced by adipocytes ad has some effects on lipid metabolism. All these data suggest a role for acylethanolamides and the endocannabinoid system in the pathophysiology of obesity, diabetes and atherosclerosis.
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PMID:[The endocannabinoid system and food intake control]. 1538 9

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.
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PMID:Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. 1581 11

The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2(-/-) phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-kappaB ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries.
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PMID:Peripheral cannabinoid receptor, CB2, regulates bone mass. 1640 42

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.
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PMID:The endocannabinoid system as an emerging target of pharmacotherapy. 1696 47

Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes. This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans.
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PMID:Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. 1851 Apr 34

The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.
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PMID:Beta-caryophyllene is a dietary cannabinoid. 1857 42

Macrophage apoptosis is an important process in the pathophysiology of atherosclerosis. Oxidized low-density lipoproteins (OxLDL) are a major component of lesions and potently induce macrophage apoptosis. Cannabinoid receptor 2 (CB2), the predominant macrophage cannabinoid receptor, modulates several macrophage processes associated with ongoing atherosclerosis; however, the role of CB2 in macrophage apoptosis is unknown. To determine if CB2 influences a macrophage apoptotic pathway relevant to atherosclerosis, we examined the effect of CB2 deficiency on OxLDL-induced macrophage apoptosis. In situ terminal transferase-mediated dUTP nick end labeling (TUNEL) analysis of resident peritoneal macrophages detected significantly fewer apoptotic CB2(-/-) macrophages than CB2(+/+) macrophages after incubation with OxLDL (27.9 +/- 4.7% vs. 61.9 +/- 8.5%, P < 0.001) or 7-ketocholesterol (7KC) (18.9 +/- 10.5% vs. 54.1 +/- 6.9%, P < 0.001), an oxysterol component of OxLDL. Caspase-3 activity; proteolytic conversion of procaspase-3; and cleavage of a caspase-3 substrate, PARP, were also diminished in 7KC-treated CB2(-/-) macrophages. Furthermore, the deactivation of the prosurvival kinase, Akt, in response to 7KC was impaired in CB2(-/-) macrophages. These results suggest that CB2 expression increases the susceptibility of macrophages to OxLDL-induced apoptosis, in part, by modulating the effect of oxysterols on the Akt survival pathway and that CB2 may influence atherosclerosis by modulating lesional macrophage apoptosis.
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PMID:Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis. 1861 16

Oxysterol-induced macrophage apoptosis may have a role in atherosclerosis. Macrophages lacking the type 2 cannabinoid receptor (CB2) are partially resistant to apoptosis induced by 7-ketocholesterol (7KC). AM-251 and SR144528 are selective antagonists of CB1 and CB2 receptors, respectively. We observed that both compounds reduce 7KC-induced apoptosis in Raw 264.7 macrophages. As oxysterol-induced macrophage apoptosis requires acyl-coenzymeA:cholesterol acyltransferase (ACAT) activity, we tested their affects on ACAT activity. AM-251 and SR144528 both reduced cholesteryl ester synthesis in unstimulated and acetylated LDL-stimulated Raw 264.7 macrophages, CB2(+/+) and CB2(-/-) peritoneal macrophages, as well as in vitro, in mouse liver microsomes. Consistent with inhibition of ACAT, the development of foam cell characteristics in macrophages by treatment with acetylated LDL was reduced by both compounds. This work is the first evidence that AM-251 and SR144528 are inhibitors of ACAT and as a result, might have anti-atherosclerotic activities independent of their affect on cannabinoid signaling.
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PMID:AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors. 1933 72

The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn's disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB(2)) receptor, which unlike the CB(1) receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB(1) receptor antagonists/inverse agonists are of therapeutic value, also CB(2) receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB(1) receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB(2) receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent anti-inflammatory effects in wild type mice but not in CB(2) receptor (Cnr2(-/-)) knockout mice. Like other CB(2) ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1beta, IL-6; IL-8 and TNFalpha) and promotes a TH(1) immune response. In this addendum, the CB(2) receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB(2) inverse agonists and agonists, independent of their G-protein signaling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.
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PMID:Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? 1970 83

Atherosclerosis remains the primary cause of heart disease and stroke, causing approximately 50% of all deaths in Western countries. The identification of promising novel anti-atherosclerotic therapies is therefore of great interest and represents a continued challenge to the medical community. Cannabinoids, such as Delta9-tetrahydrocannabinol (THC), which is the major psychoactive compound of marijuana, modulate immune functions and might therefore be of therapeutic use for the treatment of inflammatory diseases. The authors have demonstrated recently that oral treatment with low dose THC inhibits atherosclerosis progression in mice through pleiotropic immunomodulatory effects on inflammatory cells. All these effects were mediated via the cannabinoid receptor CB(2), the main cannabinoid receptor expressed on immune cells. However, these promising results are in conflict with the known health risks of smoking marijuana, as THC binds to and activates both cannabinoid receptors, CB(1) and CB(2). The identification and characterization of cannabinoid derivative that selectively activate CB(2) receptors and are devoid of adverse effects might offer a novel therapeutic strategy for the treatment of atherosclerosis.
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PMID:Towards a therapeutic use of selective CB2 cannabinoid receptor ligands for atherosclerosis. 1980 31


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