Atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol and triglyceride.
Atherosclerosis, or hardening of the arteries, is the leading cause of heart attacks, stroke, and peripheral vascular disease.
P.E. Szmitko is a Resident in the Division of General Internal Medicine, and S Verma is a Scientist and Assistant Professor in the Division of Cardiac Surgery, St Michael's Hospital, at the University of Toronto, Toronto, ON, Canada.
Competing interests: The authors declared no competing interests.
Posted: 03/17/2006; Nat Clin Pract Cardiovasc Med. 2006;3(3):116-117. © 2006 Nature Publishing Group
Obesity, particularly visceral adiposity, and its related metabolic and cardiovascular disorders, is a worldwide pandemic. The biological properties of one of the most widespread illicit drugs of abuse, marijuana, have been recruited for obesity management.
By uncovering the cellular interactions of the cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC)—the major active component of marijuana—researchers have identified new molecular pathways for treating cardiometabolic disease. Studies have demonstrated that modulation of the endocannabinoid system holds great therapeutic promise for the treatment of obesity, dyslipidemia, insulin resistance and atherosclerosis.
The endocannabinoid system contributes to the regulation of food intake, energy balance, inflammation, and lipid and glucose metabolism, and might therefore play a fundamental role in the development of obesity and atherosclerosis.
To date, two G-protein-coupled cannabinoid receptors that bind Δ9-THC with equal affinity have been identified: CB1 and CB2. The CB1 receptor, believed to mediate the psychotropic effects of cannabis and to participate in the modulation of food intake and adipogenesis, is expressed at high levels by brain cells and by several peripheral tissues including the gastrointestinal tract, the adrenal gland, the heart and adipose tissue. CB1 knockout mice exhibit a lean phenotype and appear to be resistant to diet-induced obesity and insulin resistance.
By contrast, CB2 receptors are located primarily on blood cells and immune tissues, and stimulation of these receptors with Δ9-THC results in an immunosuppressive phenotype via the modulation of immune-cell cytokine production. This molecular system might have a role in the development of obesity, the metabolic syndrome and atherosclerosis, and its modulation might form the basis of new therapeutic strategies for these pathophysiologically linked conditions.
Using apolipoprotein E knockout mice Steffens et al. demonstrated that Δ9-THC can protect against the development of atherosclerosis. CB2 receptors were expressed in both human and mouse atherosclerotic lesions, but were absent in nondiseased arteries.
Apolipoprotein E knockout mice fed a high cholesterol diet developed extensive atherosclerotic lesions in the aortic root; however, when 1 mg/kg Δ9-THC daily was added to the diet—a dose not associated with CB1 activation and psychotropic effects—a significant reduction in the progression of atherosclerotic lesions was observed. Concomitant CB2 receptor antagonist treatment abolished this observed anti-atherosclerotic effect. Even though Δ9-THC-fed mice continued to have elevated serum lipid levels, fewer inflammatory cells were recruited into atherosclerotic lesions, suggesting that Δ9-THC treatment had a beneficial effect on the inflammatory milieu.
Indeed, Steffens and co-workers demonstrated that the immunosuppressive properties of Δ9-THC interfered with the adhesion, migration, proliferation and function of immune cells involved in atherosclerotic plaque formation.
These promising results do not imply that smoking marijuana is the key to a healthy heart. Too often there is failure to translate promising results observed in murine models to human patients. The effects of Δ9-THC on atherogenesis in man have not been studied, so whether this cannabinoid does more cardiovascular harm than good remains to be seen.
The beneficial effects of Δ9-THC observed by Steffens et al. followed a U-shaped distribution with a very narrow therapeutic window, suggesting that the blood concentrations of Δ9-THC obtained from smoking marijuana would be too variable to provide sustained clinical benefit.
Furthermore, it is unlikely that purified Δ9-THC extract or marijuana would be legalized for use as an adjunctive treatment of cardiovascular disease, since both compounds could serve as drugs of abuse. In addition, smoking marijuana increases carboxyhemoglobin levels, and Δ9-THC activation of CB1 receptors induces a cardiovascular stress response; raising heart rate and blood pressure, decreasing the anginal threshold, and promoting acute coronary syndromes. Overall, smoking marijuana probably has a negative effect on the cardiovascular system.
For these reasons, therapeutic strategies using the apparent anti-inflammatory properties of Δ9-THC will probably depend upon developing specific CB2-receptor agonists, to prevent the onset of psychotropic effects. Once thoroughly tested in animal models, translation to human trials could see the positive effects reported by Steffens et al. clinically realized.
Activation of the endocannabinoid system through the CB1 receptor plays an important role in central and peripheral regulation of energy balance, body weight and food intake. Blockade of the CB1 receptor appears to offer great promise in cardiometabolic risk reduction, and 1-year results from the RIO program are very encouraging.
In this trial, 1,507 patients with a BMI of at least 30 kg/m2, or at least 27 kg/m2 or more with treated or untreated dyslipidemia, hypertension or both, received double-blind treatment with 5 mg rimonabant—a selective CB1 receptor blocker—daily, 20 mg rimonabant daily, or placebo, in addition to a hypocaloric diet.
Treatment with 20 mg rimonabant for 1 year significantly decreased total body weight and waist circumference, and produced a significant weight-independent effect on lipid parameters and several other cardiovascular risk factors. The beneficial changes to the lipid profile remained significant after adjusting for weight loss.
Furthermore, treatment resulted in a significant reduction in fasting plasma glucose, fasting plasma insulin, insulin resistance and the proportion of patients who fulfilled the criteria for the metabolic syndrome compared with placebo.
To explain the observed weight-independent effect on both lipid and glycemic variables, Van Gaal et al. hypothesized that enhanced rimonabant-induced expression of adiponectin—a cytokine that has a role in the regulation of hyperglycemia, hyperinsulinemia and fatty acid oxidation and is reduced in obese individuals—could be responsible.
Thus, by improving adipocyte function, rimonabant might contribute to beneficial changes in other adipokines, such as C-reactive protein, reinforcing the link between obesity and atherosclerosis. Further investigation of in vivo effects of rimonabant are required to fully elucidate this mechanism, especially given the concern that CB1 antagonists might raise blood pressure.
Furthermore, rimonabant appears to be a useful agent for smoking cessation, yet another cardiac risk factor. Thus, pharmacologic manipulation of cannabinoid-receptor signaling might combat the development of atherosclerosis through the treatment of obesity, the metabolic syndrome, vascular inflammation and smoking.
The beneficial effects with rimonobant appear to be consistent in over 6,600 patients enrolled in the RIO program. Patients administered this drug enjoy sustained reductions in weight, BMI and visceral adiposity, and improvements in insulin sensitivity and dyslipidemia. More importantly, the beneficial effects to counter insulin resistance, improve dyslipidemia and increase adiponectin, are only partly explained by the reduction in weight, indicating a potential direct role for CB1 in adipogenesis and lipid derangement.
The results of the RIO program and the study by Steffens et al. indicate that modulating the activity of the endocannabinoid system holds promise as an approach to treating obesity, dyslipidemia and atherogenesis. The CB1 and CB2 receptors might have opposing effects on atherogenesis: whereas central CB1-receptor blockade offers hope for atherogenic risk reduction, peripheral CB2-receptor stimulation in animals has powerful anti-atherosclerotic effects.
It is possible that a strategy of CB1-receptor antagonism and CB2-receptor agonism might emerge as the most effective treatment across the spectrum of insulin resistance and vascular disease. It is paradoxical that studying the effects of cannabis, an illicit drug that provides society with numerous social problems, could serve as the basis for novel therapeutic strategies to reduce cardiometabolic risk.
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Source: Current Topics in Medicinal Chemistry, Volume 6, Number 13, July 2006 , pp. 1401-1426(26)
Publisher: Bentham Science Publishers
Publication date: 2006-07-01
Article Date: 12 Apr 2005
The main compound in cannabis can prevent blood vessels from developing atherosclerosis, an inflammatory condition that is the primary cause of heart disease and stroke in the developed world.
A study in this week's Nature shows that disease progression is halted when mice are given low doses of delta-9-tetrahydrocannabinol (THC).
Atherosclerosis occurs when the accumulation of immune cells in blood vessels causes narrowing of the arteries, lipid accumulation and plaque formation. THC prevents immune cell recruitment by binding to proteins called CB2 receptors on the cell surface, report Franois Mach and colleagues. When given chemicals that prevent THC binding to these receptors, the therapeutic effect of THC is abolished and the mice continue to develop disease symptoms.
In the brain, THC binds to a different cell-surface receptor, called CB1. The THC doses given to the mice (about 1 milligram per kilogram body weight per day) were lower than the level required to activate the CB1 receptor, so the psychoactive effects of cannabis were not observed.
This suggests that a possible treatment for atherosclerosis might be to use pure, isolated THC - this would avoid other harmful effects of cannabis, such as increased blood pressure. "These findings should not be taken to mean that smoking marijuana is beneficial for the heart," writes Michael D. Roth in a related News and Views article.
by Plutonium Page
THC, or delta-9-tetrahydrocannabinol, is one of the many cannabinoids in marijuana. Cannabinoids have been shown to be medically beneficial as analgesics and anti-nausea agents, among other findings.
Most recently, Swiss and German researchers have shown that a very small dose of THC slows the progression of atherosclerosis (clogging of the arteries) in mice. It's a pretty amazing study, especially since atherosclerosis is the leading cause of heart disease, and strokes, in the world.
Look below the fold for details.
The study is in this week's edition of the journal Nature. You can get the full text of the article for $30 if you aren't a subscriber, or you can just read the handy news release:
A compound derived from the cannabis plant protects blood vessels from dangerous clogging, a study of mice has shown. The discovery could lead to new drugs to ward off heart disease and stroke.
The compound, called delta-9-tetrahydrocannabinol (THC), combats the blood-vessel disease atherosclerosis in mice. This disease occurs when damage to blood vessels, by nicotine from cigarettes, for example, causes an immune response that leads to the formation of fatty deposits in arteries.
These deposits form because the immune cells can linger too long, recruiting others and leading to an inflamed blockage that snares fatty molecules. The disease is the leading cause of heart disease and stroke in the developed world.
THC seems to tone down this immune response, report François Mach of the University Hospital Geneva, Switzerland and his colleagues. The compound binds to a protein called CB2 that is present on the surfaces of certain immune cells.
In addition to CB2, there is another receptor called CB1. Simply put, when THC binds to that one, you get high. Anyway, the researchers in this study proved that THC had to bind to CB2 for it to slow atherosclerosis. It didn't have any effect when it bound to CB1 (except possibly get the mice stoned).
The news release goes on to point out that:
The benefits for atherosclerosis occurred only at a certain dosage, Mach adds. At higher and lower doses, THC has no therapeutic effect on blood vessels, he says. He notes the similarly moderated effects of alcohol on heart disease, adding that a single glass of Bordeaux may reduce risk while overindulgence can increase it.
The team also emphasises that the THC dose required to protect blood vessels is lower, relative to body weight, than that which would produce the mind-altering altering effects of cannabis in humans. "This paper has nothing to do with smoking marijuana," Mach stresses.
The researchers speculate that perhaps cannabinoids could be used in conjunction with statins, which lower blood cholesterol levels.
Obviously, the effects of THC are complex. However, the volume of literature that indicates the medical benefits of marijuana is obviously growing. Someday, hopefully, lawmakers in all states will be convinced that marijuana should be decriminalized for medical use.
One of the most consistent effects of cannabis intoxication is an increased heart rate. For this reason alone it would not be normally recommended for patients with cardiovascular problems. However, THC also acts as a smooth-muscle relaxant, relaxing the walls of the arteries, which can result in lower blood pressure and increased blood flow to the tissues. The effect taken together is analogous to a car changing down a gear.
Cannabis intoxication has been found to reduce the level of exercise which can be tolerated before the onset of angina.to a greater extent than a high-nicotine tobacco cigarette. Cardiovascular symptoms have been attributed to cannabis use, either alone (stroke), or in combination with alcohol and cocaine.
The presence and action of CB1 cannabinoid receptors in arterial tissue was described by Bilginger et al, who reported: "the data demonstrate that cannabinoid signalling is involved with the regulation of the microvascular environment" Cannabinoids such as CBD and the synthetic HU-211 have been shown to reduce ischaemic cell damage following cardiac arrest or stroke. CBD also counteracts the increase in heart-rate associated with THC - THC and CBN both appear to increase heart rate, while CBD tends to decrease heart rate.
There is conflicting evidence as to whether changes in cardiovascular function are related to myocardial contractility. Animal studies are conflicting, the effect in dogs appears opposite to that in humans. Part of the increase in heart rate can be counteracted by use of beta-blocker drugs, but not by opiate antagonists such as Naloxone.
From a clinical study of long-term marijuana smokers, Tashkin et al concluded "in long-term heavy users of cannabis, marihuana has no significant effect on myocardial contractility independent of its effect on heart rate."
Early studies on rats bred for high blood pressure[xviii] found that THC reduced levels of blood pressure, and that tolerance developed to this effect[xxi]. Mechoulam predicted in 1978 "Numerous synthetic cannabinoids are currently being investigated as analgetics and as sedative-relaxants." Zaugg & Kyncl reported "hydroxyacetyl and gamma-hydroxybutyryl (cannabinol) derivatives were potent antihypertensive agents (minimum effective dose, 3-5 mg/kg, orally) of the same order of activity as the highly CNS-active N-propargyl derivatives"
Hanus et al[xxiv] reported that the specific CB2 receptor agonist HU-308 "reduces blood pressure... The hypotension... produced by HU-308 (is) blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A.
These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension..." Garcia reported "Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output.
Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB(1) antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide."
Gardiner et al[xxvi], rats studying the effects of the cannabinoid receptor agonist WIN 55212-2 in normal (HSD) and hypertensive (TG), concluded "Collectively, the results indicate that the predominant cardiovascular effects of WIN 55212-2 in conscious HSD and TG rats (i.e., pressor and vasoconstrictor actions) can be attributed largely to indirect, pentolinium-sensitive mechanisms, which appear to differ little in the normotensive and hypertensive state, at least in conscious animals.
Under the conditions of our experiments, signs of cannabinoid-induced vasodilatation were modest." Studying anandamide in anaesthetised and conscious rats, Gardiner et al[xxvii] reported "At all doses of anandamide, there was a significant, short-lived increase in mean arterial blood pressure associated with vasoconstriction in renal, mesenteric and hindquarters vascular beds.
The higher doses (2.5 and 3 mg kg(-1)), caused an initial, marked bradycardia accompanied, in some animals, by a fall in arterial blood pressure which preceded the hypertension. In addition, after the higher doses of anandamide, the hindquarters vasoconstriction was followed by vasodilatation... None of the cardiovascular actions of anandamide were influenced by the CB(1)-receptor antagonist, AM 251"
Jarai & Kunos[xxviii] noted "cannabinoids were found to be potent CB1-receptor dependent vasodilators in the coronary and cerebrovascular beds" concluding "the endogenous cannabinoid system plays an important role in cardiovascular regulation, and pharmacological manipulation of this system may offer novel therapeutic approaches in a variety of pathological conditions." Wagner et al[xxix] report "Activation of peripheral cannabinoid CB(1) receptors elicits hypotension" and noted "We conclude that cannabinoids elicit profound coronary and cerebral vasodilation in vivo by direct activation of vascular cannabinoid CB(1) receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, the action of a non-cannabinoid metabolite."
However, in a review article for the Bulletin on Narcotics, Husan & Khan warned "The use of cannabis causes prominent and predictable effects on the heart, including increased work-load, increased plasma volume and postural hypotension, which could impose threats to the cannabis users with hypertension, cerebrovascular disease or coronary arteriosclerosis."
Lake et al[xxxi] noted "in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC)" Krowicki et al[xxxii] found that, in anaesthetised rats "Intravenously administered delta9-THC evoked ... bradycardia, and hypotension"
The picture is slowly becoming clearer, indicating that endo-cannabinoids modify aspects of blood flow at a subtle local level. In a 2001 review, Schiffrin noted "The endothelium produces a variety of substances that play important roles in regulation of the circulation and vascular wall homeostasis. The control of blood vessel wall homeostasis is achieved via production of vasorelaxants and vasoconstrictors. Among the vasorelaxants are ... metabolites of arachidonic acid like epoxyeicosatrienoic acids, and endocannabinoids)"
Matthew & Wilson found "In experienced marijuana smokers, marijuana smoking was accompanied by a significant bilateral increase in cerebral blood flow (CBF) especially in the frontal regions and cerebral blood velocity." Tunving et al, studying long-term cannabis users found decreases in cerebral blood flow during the early stages of detoxification, reverting to normal after 9-60 day follow-up. Similar results were found by Lundqvist et al - "Cerebral blood flow (CBF) was measured in 12 long-term cannabis users shortly after cessation of cannabis use (mean 1.6 days).
The findings showed significantly lower mean hemispheric blood flow values and significantly lower frontal values in the cannabis subjects compared to normal controls" Ellis et al found "Anandamide (AN) and delta 9-THC similarly induced a dose-dependent dilation (of cerebral arterioles) starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation"
Bloom et al found different areas of the brain to have different blood-flow responses to THC · "Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured." Stein et al in the rat, an O"Leary et al[xl] in human recreational users, also found wide variations in cerebrovascular response in different brain regions.
There are a number of case studies describing patients who have suffered strokes following or during cannabis use, some, but not all,of these cases can be explained by use of other drugs (alcohol or stimulants). Cooles & Michaud[xli] report a case history of a patient suffering a stroke following a heavy bout of cannabis smoking.
Alvaro et al reported another case history "of a young man and heavy cannabis smoker who suffered posterior cerebral artery infarction during his first episode of coital headache"In a further case history, Lawson & Rees reported "A 22-year-old man with a five-year history of drug and alcohol abuse presented with a left hemiparesis preceded by three transient ischaemic attacks, two of which occurred whilst smoking cannabis" although in response, McCarrom & Thomas[xliv] stressed the likely role of alcohol or other drugs in the etiology of such strokes.
Mouzak et al described "Three male patients (mean age 24.6 years) who were heavy cannabis smokers presented with transient ischemic attacks (TIA) shortly after cannabis abuse... The urine analysis was positive for cannabis metabolites.
There were no other abnormal findings in the rest of the meticulous and thorough study of all 3 patients, which leads to the conclusion that cannabis was the only risk factor responsible for the observed TIA, contradictory to other studies, which support that cannabis is a 'safe' drug."
However, it is clear that cannabinoids have a variety of cerebrovascular effects, increasing the blood supply to the brain, and can protect against potentially fatal brain cell death following a stroke by reducing tumour necrosis factor, which causes self-destruction in exposed cells. The use of cannabinoids for treatment of brain damage arising from strokes is reaching an advanced stage of the licensing process, Job[xlvii] reported in 2000 "Dexanabinol is a non-psychotropic cannabinoid NMDA receptor antagonist under development by Pharmos Corp for the potential treatment of cerebral ischemia... cardiac failure, head injury and multiple sclerosis (MS)... it is in phase III trials for traumatic brain injury...
Pharmos estimates that the worldwide market for dexanabinol in the treatment of severe head trauma may reach $1 billion per year" Leker et al investigated the effect of dexanabinol, a synthetic cannabinoid which is a NMDA antagonist, with antioxidant and anti-tumour necrosis factor alpha properties, on the levels of brain damage (infarct) following experimentally induced ischaemic strokes in rats, finding "Dexanabinol significantly decreased infarct volumes.
It also significantly lowered TNFalpha levels in the ipsilateral hemisphere although not to the level of sham operated rats... In conclusion, dexanabinol may be a pluripotent cerebroprotective agent."
Panikashvili et alreported "Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage. Protective mechanisms to attenuate damage are also set in motion. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid... after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. We administered synthetic 2-AG to mice after CHI and found significant reduction of brain oedema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141761A, an antagonist of the CB1 cannabinoid receptor."
Belayev et al found the synthetic cannabinoid HU-211 to be "an effective drug in protecting against the effects of focal ischemia-induced (blood-brain barrier) disruption in the rat and suggest that the drug may be an effective treatment against the ischemic cell death and BBB disruption that can occur clinically following a stroke or cardiac arrest." Nagayama et al[li] noted "R(+)-WIN 55212-2, a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats.
The less active enantiomer S(-)-WIN 55212-3 was ineffective, and the protective effect ... was blocked by (a) specific central cannabinoid (CB1) cannabinoid receptor antagonist . R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in vitro effect was not stereoselective and was insensitive to CB1 and CB2 receptor antagonists" concluding "Cannabinoids may have therapeutic potential in disorders resulting from cerebral ischemia, including stroke, and may protect neurons from injury through a variety of mechanisms."
In a 1999 review of advances in cannabinoid research, Mechoulam noted "A synthetic cannabinoid, HU-211, is in advanced clinical tests against brain damage caused by closed head injury. It may prove to be valuable against stroke and other neurological diseases" Guzman et al observed "One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision.
Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells." Jin et al concluded "These findings are consistent with a neuroprotective role for endogenous cannabinoid signaling pathways and with a potential therapeutic role in stroke for drugs that activate CB1 receptors"
Cannabis increases heart rate in na•ve users although tolerance develops to this effect.
Cannabinoids can also reduce blood pressure via arteriollar dilatation in a variety of tissues, although the effect on blood flow varies at a local level, with some organs or brain regions experiencing vasoconstriction, others vasodilation.
In the withdrawal phase following cessation of chronic use, cerebral blood flow may be significantly reduced.
Cannabis use has been implicated as a causative factor in a small number of patients suffering strokes or transient ischaemic attacks, and may represent a risk factor to susceptible individuals.
However cannabinoids, in particular CB1-receptor agonists, have been shown to protect against nerve cell death following stroke, and dexanabinol at an advanced stage of the licensing process as a drug to be administered to victims of stroke or closed-head injuries to minimise the long-term brain damage caused by such events, and to improve survival and recovery prospects.
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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 atherosclerosi
Division of Cardiology, Department of Medicine, Foundation for Medical Research, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland.
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.
Takeda S, Usami N, Yamamoto I, Watanabe K
Drug Metab D
The inhibitory effect of nordihydroguaiaretic acid (NDGA), a non-selective lipoxygenase (LOX) inhibitor, -mediated 15-LOX inhibition has been reported to be affected by modification of its catechol ring such as methylation of the hydroxyl group. Cannabidiol (CBD), one of the major components of marijuana, is known to inhibit LOX activity.
Based on the phenomenon observed in NDGA, we investigated whether or not methylation of CBD affects its inhibitory potential against 15-LOX, since CBD contains a resorcinol ring, which is an isomer of catechol. Although CBD inhibited 15-LOX activity with an IC50 value (50% inhibition concentration) of 2.56 microM, its mono-methylated and di-methylated derivatives, CBD-2'-monomethyl ether (CBDM) and CBD-2',6'-dimethyl ether (CBDD) inhibited 15-LOX activity more strongly than CBD. The number of methyl groups in the resorcinol moiety of CBD (as a prototype) appears to be a key determinant for potency and selectivity in inhibition of 15-LOX. The IC50 value of 15-LOX inhibition by CBDD is 0.28 microM, and the inhibition selectivity for 15-LOX (i.e., the 5-LOX/15-LOX ratio of IC50 values) is more than 700.
Among LOX isoforms, 15-LOX is known to be able to oxygenate the cholesterol esters in the low density lipoprotein (LDL) particle (i.e., the formation of oxidized LDL). Thus, 15-LOX is suggested to be involved in developing atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.
ispos 2009 Apr 30.
The endocannabinoids are a family of lipid neurotransmitters that engage the same membrane receptors targeted by tetrahydrocannabinol and that mediate retrograde signal from postsynaptic neurons to presynaptic ones.
Discovery of endogenous cannabinoids and studies of the physiological functions of the cannabinoid system in the brain and body are producing a number of important findings about the role of membrane lipids and fatty acids. The role of lipid membranes in the cannabinoid system follows from the fact that the source and supply of endogenous cannabinoids are derived from arachidonic acid.
The study of molecules which influence the cannabinoid system in the brain and body is crucial in search of medical preparations with the therapeutic effects of the phytocannabinoids without the negative effects on cognitive function attributed to cannabis. Basic information about function and role of the endocannabinoid system is summarized in the paper; possible therapeutic action of cannabinoids, effects on atherosclerosis specially, is described at the close.
April 6, 2005 -- The active ingredient in marijuana that produces changes in brain messages appears to fight atherosclerosis -- a hardening of the arteries.
But puffing pot probably won't help. The findings, reported in the journal Nature, "should not be taken to mean that smoking marijuana is beneficial for the heart," says Michael Roth, MD, a professor of medicine at UCLA medical school.
It takes a very specific amount of THC -- marijuana's key chemical -- to help the arteries. That dose is too low to produce mood-altering effects in the brain, according to the new study.
"It would be difficult to achieve such specific concentrations in the blood by smoking marijuana," Roth explains in a Nature editorial.
Smoking marijuana can speed up the pulse and raise blood pressure (followed by a sudden fall upon standing or walking), Roth notes.
"These effects lower the exercise threshold for chest pain [angina], and are an independent risk factor for heart attack and stroke," he writes. Inhaling marijuana smoke can also impair oxygen delivery via the blood, says Roth.
The best way to take advantage of THC's artery-protecting effects may be by developing new prescription drugs "rather than using marijuana or oral THC as medicines," he writes.
The new study was conducted on mice, not people. First, mice went on an 11-week fatty diet designed to clog their arteries. For the last six weeks of the diet, some mice also got an orally administered low dose of THC along with the high-fat food.
Afterward, the mice who had received THC had fewer signs of atherosclerosis. None of those mice died during treatment or showed unhealthy behavior, says the study.
The results may be due to THC's anti-inflammatory properties, write the researchers, who included François Mach, MD, of the cardiology division at University Hospital in Geneva, Switzerland. Inflammation has been shown to be associated with the development of atherosclerosis.
The researchers took a closer look at THC. They knew the chemical has two receptors, called CB1 (mainly found in the brain) and CB2 (mostly found outside the brain).
When they used another drug to block CB2 receptors in the mice, THC couldn't protect the animals' arteries. As for the CB1 receptors, the THC dose used in the study was too low to affect them, so no "high" was created.