Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression.

Fig. 1

“Cannabinoids are a group of compounds found in the marijuana plant (Cannabis sativaL.). Marijuana has been used both for recreational and medicinal purposes for several centuries.

Cannabinoids have been shown to be effective in the treatment of nausea and vomiting associated with cancer chemotherapy, anorexia and cachexia seen in HIV/AIDS patients, as well as neuropathic pain, and spasticity in multiple sclerosis.

More recently, the anti-inflammatory properties of cannabinoids are drawing significant attention. In the last 15 years, studies with marijuana cannabinoids led to the discovery of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, which make up what is known as the endocannabinoid system.

Cannabinoids are a group of compounds present in Cannabis plant (Cannabis sativa L.). They mediate their physiological and behavioral effects by activating specific cannabinoid receptors. With the recent discovery of the cannabinoid receptors (CB1 and CB2) and the endocannabinoid system, research in this field has expanded exponentially.

Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma.

Cannabinoid receptor 1 (CB1) is mainly expressed on the cells of the central nervous system as well as in the periphery. In contrast, cannabinoid receptor 2 (CB2) is predominantly expressed on immune cells. The precise mechanisms through which cannabinoids mediate immunosuppression is only now beginning to be understood…

In this review, we will focus on apoptotic mechanisms of immunosuppression mediated by cannabinoids on different immune cell populations and discuss how activation of CB2 provides a novel therapeutic modality against inflammatory and autoimmune diseases as well as malignancies of the immune system, without exerting the untoward psychotropic effects…

…cannabinoids do induce apoptosis in immune cells, alleviating inflammatory responses and protecting the host from acute and chronic inflammation.

The cumulative effect of cannabinoids on all cell populations of the immune system can be beneficial, when there is a need for immune suppression.

For example, in patients with autoimmune diseases such as multiple sclerosis, arthritis and lupus, or in those with septic shock, where the disease is caused by activated immune cells, targeting the immune cells via CB2 agonists may trigger apoptosis and act as anti-inflammatory therapy.

CB2 select agonists are not psychoactive and because CB2 is expressed primarily in immune cells, use of CB2 agonists could provide a novel therapeutic modality against autoimmune and inflammatory diseases.

In addition to the use of exogenous cannabinoids, in vivo manipulation of endocannabinoids may also offer novel treatment opportunities against cancer and autoimmune diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005548/

Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.

“The cannabinoid system is immunomodulatory and has been targeted as a treatment for the central nervous system (CNS) autoimmune disease multiple sclerosis.

Using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we investigated the role of the CB(1) and CB(2) cannabinoid receptors in regulating CNS autoimmunity…

Together, our results demonstrate that the cannabinoid system within the CNS plays a critical role in regulating autoimmune inflammation, with the CNS directly suppressing T-cell effector function via the CB(2) receptor.”

http://www.ncbi.nlm.nih.gov/pubmed/17401376

Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor.

The cannabinoid system is evolutionally conserved and is present in invertebrates and vertebrates. One of the best-studied cannabinoids is Δ9-tetrahydrocannabinol (THC), the predominant active component of Cannabis sativa or marijuana.

The marijuana plant has been exploited by humans since their early history and was used for centuries in Asian medicine to reduce the severity of pain, inflammation and asthma. However, only recently have the mechanisms of the medicinal properties of THC begun to be understood. This understanding is largely due to the identification and cloning of two cannabinoid receptors.

The cannabinoid system is now recognized as a regulator of both the nervous and immune systems.

Although marijuana has been used for centuries for the treatment of a variety of disorders, its therapeutic mechanisms are only now being understood.

The best-studied plant cannabinoid, delta9-tetrahydrocannabinol (THC), produced by Cannabis sativa and found in marijuana, has shown evidence of being immunosuppressive in both in vivo and in vitro.

These studies are theoretically in agreement with the suggestions of others that cannabinoid receptor agonists would be beneficial for the treatment of MS in humans.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219523/

A biosynthetic pathway for anandamide

“The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released “on demand” by neurons in the brain. Anandamide is also generated by macrophages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE-PLD).

Here we document a biosynthetic pathway for anandamide in mouse brain…

Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC/phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target.

The observed exclusive role of the PLC/phosphatase pathway in LPS-induced AEA synthesis may offer therapeutic targets for the treatment of these conditions.

Furthermore, cannabinoids have immunosuppressive effects in autoimmune models of multiple sclerosis and diabetes, and mice deficient in CB1 receptors show increased susceptibility to neuronal damage found in autoimmune encephalitis…”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1557387/#!po=23.3333

Multiple sclerosis may disrupt endocannabinoid brain protection mechanism

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“Since the discovery of the endocannabinoids [eCB; anandamide and 2-arachidonoylglycerol (2-AG), various pathological conditions were shown to increase the eCB tone and to inhibit molecular mechanisms that are involved in the production, release, and diffusion of harmful mediators such as proinflammatory cytokines or excess glutamate.

In this issue of PNAS, Witting et al.  demonstrate that, unexpectedly and contrary to the effects of other brain diseases, cell damage induced by experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease widely used as a laboratory model of multiple sclerosis (MS), does not lead to enhancement of eCB levels, although the cannabinoid receptors remain functional.

Nearly two decades ago, Lyman et al.  reported that Δ9-THC, the psychoactive component of marijuana, suppresses the symptoms of EAE. A few years later, Wirguin et al. reported the same effect by Δ8-THC, a more stable and less psychotropic analogue of Δ9-THC.

Thus, THC was shown to inhibit both clinical and histological signs of EAE even before the endocannabinoids were described.

THC was also shown to control spasticity and tremor in chronic relapsing EAE, a further autoimmune model of MS , and to inhibit glutamate release via activation of the CB1-cannabinoid receptor in EAE. Moreover, mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration after immune attack in EAE.

Thus, the brain loses some of its endogenous neuroprotective capacity, but it may still respond to exogenous treatment with 2-AG or other CB1 agonists. Assuming that the biochemical changes taking place in the EAE model of MS are similar to those in MS itself, these results represent a biochemical-based support to the positive outcome noted with cannabinoid therapy in MS.

These data suggest that the high level of IFN-γ in the CNS, noted in mice with EAE, disrupts eCB-mediated neuroprotection, while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat MS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458835/

The role of the endocannabinoid system in atherosclerosis.

“Our current understanding of the pathophysiology of atherosclerosis suggests a prominent role for immune responses from its initiation through its complications. Given the increasing prevalence of cardiovascular risk factors worldwide, there is an urgent need to better understand the underlying mechanisms to improve current treatment protocols.

A growing body of evidence suggests that endocannabinoid signalling plays a critical role in the pathogenesis of atherogenesis and its clinical manifestations. Blocking CB(1) receptors has been shown to mediate not only weight reduction, but also several cardiometabolic effects in rodents and humans, indicating a potential relevance for the process of atherosclerosis.

Activation of CB(2) receptors with Delta(9)-tetrahydrocannabinol (THC) has been shown to inhibit atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment.

In conclusion, the precise role of the endocannabinoid system during atherosclerosis is not yet understood.”

http://www.ncbi.nlm.nih.gov/pubmed/18426500

http://www.thctotalhealthcare.com/category/atherosclerosis-2/

Cannabinoid receptors in atherosclerosis.

“…cannabinoid receptors are potential targets for the treatment of atherosclerosis…

Cannabinoids, such as Delta9-tetrahydrocannabinol, the major psychoactive compound of marijuana… was shown to inhibit disease progression through pleiotropic effects on inflammatory cells.

The development of novel cannabinoid receptor ligands that selectively target CB2 receptors or pharmacological modulation of the endocannabinoid system might offer novel therapeutic strategies in the treatment of atherosclerosis.

The immunomodulatory capacity of cannabinoids is now well established and suggests a broad therapeutic potential of cannabinoids for a variety of conditions, including atherosclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/16960500

http://www.thctotalhealthcare.com/category/atherosclerosis-2/

“Activation of CB(2) receptors with Delta(9)-tetrahydrocannabinol (THC) has been shown to inhibit atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment.”

http://www.ncbi.nlm.nih.gov/pubmed/18426500

Cannabinoid receptors in acute and chronic complications of atherosclerosis

“Atherosclerosis is a chronic inflammatory disease that is the primary cause of myocardial infarction and stroke, which occur after sudden thrombotic occlusion of an artery.

A growing body of evidence suggests that cannabinoid signalling plays a fundamental role in atherosclerosis development and its clinical manifestations. Thus, CB2 receptors are protective in myocardial ischaemia/reperfusion and implicated in the modulation of chemotaxis, which is crucial for the recruitment of leukocytes during inflammation.

Delta-9-Tetrahydrocannabinol (THC)-mediated activation has been shown to inhibit atherosclerotic plaque progression in a CB2 dependent manner.

It is tempting to suggest that pharmacological modulation of the endocannabinoid system is a potential novel therapeutic strategy in the treatment of atherosclerosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219535/

Peripheral and intra-dorsolateral striatum injections of the cannabinoid receptor agonist WIN 55,212-2 impair consolidation of stimulus-response memory.

“The endocannabinoid system plays a major role in modulating memory. In the present study, we examined whether cannabinoid agonists influence the consolidation of stimulus-response/habit memory, a form of memory dependent upon the dorsolateral striatum (DLS)…

The results indicate that peripheral or intra-DLS administration of a cannabinoid receptor agonist impairs consolidation of DLS-dependent memory. The findings are discussed within the context of previous research encompassing cannabinoids and DLS-dependent learning and memory processes, and the possibility that cannabinoids may be used to treat some habit-like human psychopathologies (e.g. posttraumatic stress disorder) is considered.”

http://www.ncbi.nlm.nih.gov/pubmed/24838065

Prevention of Alzheimer’s Could Hinge on Marijuana Science

Alzheimers Disease includes reduced brain activity and function (red areas above), the result of years of accumulated damage. Molecules in pot seem to prevent this damage.

“The British Journal of Pharmacologyhas published a paper that concludes that the ingredients in marijuana likely work to prevent the onset of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and age-related dementia.

Smoking, vaping, or eating the pot molecules THC and CBD directly effects nerve cell function, resulting in reduced chronic brain inflammation, reduced oxidative stress, and reduced cellular dysfunction — all the while promoting stability of the human body’s internal environment (homeostasis) and healthy brain cells (neurotrophic support)…

Pot likely prevents Alzheimer’s and other neurodegenerative diseases at the individual cell level. Molecules in pot like THC and CBD (called cannabinoids) plug into a primal, chemical signaling system in cells called “the endocannabinoid system.” Cannabinoids dampen inflammation, protect cells from oxidative damage, and promote cell health on a number of levels, the paper shows.

Manipulating the endocannabinoid system will likely be a key to preventing or curing a bunch of neurodegenerative disorders, the paper concludes.”

http://www.eastbayexpress.com/LegalizationNation/archives/2014/05/13/prevention-of-alzheimers-could-hinge-on-marijuana-science

“Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation”  http://www.jneurosci.org/content/25/8/1904.long

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/