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/

Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy.

“The cannabinoid receptor type 2 (CB2) has protective effects in chronic degenerative diseases. Our aim was to assess the potential relevance of the CB2 receptor in both human and experimental diabetic nephropathy (DN)…

The CB2 receptor is expressed by podocytes, and in experimental diabetes, CB2 beneficialactivation ameliorates both albuminuria and podocyte protein loss, suggesting a protective effect of signaling through CB2 in DN.

In conclusion, our findings may have important implications for DN. The beneficial effect… makes CB2 agonism an attractive new strategy for the treatment of DN. CB2 activation may also positively affect other diabetes-related complications as CB2 agonists may, under certain conditions, delay progression of atherosclerotic lesions and ameliorate diabetes-induced neuropathic pain…

Our study may thus pave the way for future clinical trials on CB2 agonists in humans.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161308/

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.

“Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity.

Cannabidiol (CBD), a non-psychoactive cannabinoid has been previously shown by us to suppress cell-mediatedautoimmune joint destruction in an animal model of rheumatoid arthritis.

We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice…

Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.”

http://www.ncbi.nlm.nih.gov/pubmed/16698671

Cannabidiol arrests onset of autoimmune diabetes in NOD mice.

Figure 2

“Cannabidiol (CBD) is a potent anti-inflammatory agent. It is effective in supressing IFN-γ and TNF-α production and progression of autoimmune Th1-mediated rheumatoid arthritis by inhibition of T cell proliferation. This observation led us to investigate the possible effects of CBD on additional autoimmune diseases.

We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice.

In the present study we show that administration of CBD to 11-14 week old female NOD mice… ameliorates the manifestations of the disease…

CBD was extracted from Cannabis resin (hashish)…

Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes.

CBD is not psychoactive and has anti-inflammatory and anti autoimmune properties.

Based on the above presented results, on the previously documented anti-inflammatory effects of CBD and on its clinical safety, it seems reasonable to consider the use of CBD for controlling type 1 diabetes at an early stage of the disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270485/

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

Study: Marijuana Appears to Slow Cancer Growth in Laboratory Setting -FOXNEWS

“Certain marijuana components may suppress the tumors of highly invasive cancers, a new study finds.

In laboratory tests, cannabinoids, the active components in marijuana, were found to slow the spread of lung and cervical cancer tumors, according to researchers Robert Ramer and Burkhard Hinz of the University of Rostock in Germany.

Proponents of medical marijuana believe that cannabinoids reduce the side effects of cancer treatment, such as pain, weight loss and vomiting.

The study, published in the Jan. 2 issue of the Journal of the National Cancer Institute, finds that the compounds may also have an anticancer effect;

Click here for the study.

In addition to suppressing tumor cell invasion, cannabinoids also stimulated the expression of TIMP-1, an inhibitor of a group of enzymes involved in tumor cell invasion.

“To our knowledge, this is the first report of TIMP-1-dependent anti-invasive effects of cannabinoids,” the authors wrote. “This signaling pathway may play an important role in the antimetastatic action of cannabinoids, whose potential therapeutic benefit in the treatment of highly invasive cancers should be addressed in clinical trials.””

https://www.foxnews.com/story/study-marijuana-appears-to-slow-cancer-growth-in-laboratory-setting

“Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.” https://academic.oup.com/jnci/article/100/1/59/2567700

Cannabidiol (CBD) Shown To Kill Breast Cancer Cells -Cafemom

“Cannabidiol (CBD) has been on the receiving end of a lot of attention from the scientific community for several decades now.

However, it is only now that we are really starting to begin to get a grasp on how wonderful this cannabinoid truly is.

study from 2011 states that cannabidiol is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. However, the exact molecular mechanism through which CBD works in this capacity is yet to be understood. The study, titled “Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy,” focuses on how CBD can kill breast cancer cells. Breast cancer is the second leading cause of cancer-related death in women in the United States.

What the scientists found was that CBD influences apoptosis by interacting with a key protein, called beclin-1, found within the cancerous cell. Beclin-1 is also known to play a key role in autophagy, or cellular self-degradation of non-vital components, which may lead to programmed cell death. This causes a distortion of the electrical signals between the outer mitochondrial membrane and the rest of the cell, disrupting the transfer to the cell interior of certain molecules that are necessary for metabolism. What this means is that the cell cannot transfer energy, and the cell starves to death, and in doing so activates the self-destruction process of apoptosis.

The study concludes by stating, “In summary, we showed that CBD, a plant-derived cannabinoid, preferentially kills breast cancer cells by inducing ER stress, inhibiting mTOR signaling, enhancing ROS generation, and mediating a complex balance between autophagy and mitochondria-mediated apoptosis in MDA-MB-231 breast cancer cells. These findings support the continued exploration of CBD as an alternative agent for breast cancer treatment.””

http://www.cafemom.com/group/99198/forums/read/19190923/Cannabidiol_CBD_Shown_To_Kill_Breast_Cancer_Cells

“Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-talk between Apoptosis and Autophagy… In summary, we showed that CBD, a plant-derived cannabinoid, preferentially kills breast cancer cells…” http://mct.aacrjournals.org/content/10/7/1161.full

http://www.thctotalhealthcare.com/category/breast-cancer/

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/