“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.”
“We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.
Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.”
“The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments.
On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target.
The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately.
Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2.
Most of these influence cell proliferative activity.
Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis.
The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.”
“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis.
Peroxisome proliferator-activated receptor-alpha (PPAR-α) and cannabinoid receptor 2 (CB2) crucially impact the modulation of inflammation.
N-Oleoylethanolamine (OEA), a natural agonist of PPAR-α, can also up-regulate the expression of CB2 in human umbilical vein endothelial cells (HUVECs) and further shows an antiatherosclerotic effect.
Our study was designed to determinate whether OEA could inhibit inflammation in HUVECs induced by tumor necrosis factor-α (TNF-α) and to identify the mechanism of OEA function.
These results suggest that OEA exerts anti-inflammatory and anti-adhesive effects on HUVECs.”
“15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis.
We have recently reported that cannabidiol-2′,6′-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation.
The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway.
These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.
In sum, these findings suggest that CBDD may be a useful adjuvant in the treatment of atherosclerosis as well as an experimental tool for analyzing the mechanistic details of PUFAs oxygenation by 15-LOX.”
“Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.” http://www.ncbi.nlm.nih.gov/pubmed/19406952
“Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques.
The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages.
The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques.”
“Low dose helps combat formation of arterial blockages.
A compound derived from the cannabis plant protects blood vessels from dangerous clogging, a study of mice has shown.
The compound, called delta-9-tetrahydrocannabinol (THC), combats the blood-vessel disease atherosclerosis in mice.
The discovery could lead to new drugs to ward off heart disease and stroke.”
“Cannabinoids, components of the Cannabis sativa (marijuana) plant, are known to exert potent anti-inflammatory, immunomodulatory and analgesic effects through activation of cannabinoid-1 and -2 (CB1 and CB2) receptors located in the central nervous system and immune cells.
The limitation of the therapeutic utility of the major cannabinoid, Δ9-tetrahydrocannabinol, is the development of psychoactive effects through central nervous system CB1 receptor. In contrast, cannabidiol (CBD), one of the most abundant cannabinoids of Cannabis sativa with reported antioxidant, anti-inflammatory, and immunomodulatory effects is well tolerated without side effects when chronically administered to humans and is devoid of psychoactive properties due to a low affinity for the CB1 and CB2 receptors.
A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes.
In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-κB activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs).
HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-κB activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs.
Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment.
Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis.
Collectively, our results suggest that the nonpsychoactive cannabinoid CBD have significant therapeutic benefits against diabetic complications and atherosclerosis by attenuating HG-induced mitochondrial superoxide generation, increased NF-κB activation, upregulation of iNOS and adhesion molecules, 3-NT formation, monocyte-endothelial adhesion, TEM of monocytes, and disruption of the endothelial barrier function.
This is particularly encouraging in light of the excellent safety and tolerability profile of CBD in humans.”
“Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.
In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.
Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis.
Current treatments ameliorate the symptoms but are not curative.
Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration.
To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.
Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.”
“Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency.
The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models.
The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some.
In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors.
Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases.
In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders.
Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.”