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/

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/

Cannabinoid receptor 2 expression in human proximal tubule cells is regulated by albumin independent of ERK1/2 signaling.

“The cannabinoid receptor type 2 (CB2) is reduced in podocytes of animals and humans with Type 2 Diabetes Mellitus (T2DM), with activation of CB2 ameliorating albuminuria in animals. As albuminuria also is due to proximal tubule dysfunction, the aim of this study is to investigate tubular expression of CB2 under diabetic conditions in addition to the cell signaling pathways that underlie these changes…

We have demonstrated that internalization of albumin is required to reduce CB2 mRNA and protein expression in proximal tubules in vitro. Consequently, altered expression of CB2 in both the podocytes and tubules may contribute to the albuminuria observed in T2DM.”

http://www.ncbi.nlm.nih.gov/pubmed/24280624

Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes.

“Endocannabinoids exert their biological effects via interaction with G-protein coupled cannabinoid receptors CB1 and CB2. Polymorphisms in the CNR1 gene (encoding CB1 receptor) were previously found to be associated with dyslipidemia and cardiovascular diseases. We investigated a role of the polymorphism in CNR1 gene in type 2 diabetes and its complications…

The novel finding of our study is the association of the G1359A polymorphism with diabetic nephropathy and diabetic retinopathy in patients with T2DM. This polymorphism was also associated with cardiovascular disease in the patient group.”

http://www.ncbi.nlm.nih.gov/pubmed/24075694

CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release.

“Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability…

We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles.

These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.”

http://www.ncbi.nlm.nih.gov/pubmed/24089517

Cannabinoids alter endothelial function in the Zucker rat model of type 2 diabetes.

“Circulating levels of anandamide are increased in diabetes, and cannabidiol ameliorates a number of pathologies associated with diabetes. The aim of the present study was to examine how exposure to anandamide or cannabidiol might affect endothelial dysfunction associated with Zucker Diabetic Fatty rats…

These studies suggest that increased circulating endocannabinoids may alter vascular function both positively and negatively in type 2 diabetes, and that part of the beneficial effect of cannabidiol in diabetes may be due to improved endothelium-dependent vasorelaxation.”

http://www.ncbi.nlm.nih.gov/pubmed/24120371

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/

Marijuana Compound May Help Stop Diabetic Retinopathy

“A compound found in marijuana won’t make you high but it may help keep your eyes healthy if you’re a diabetic, researchers say. Early studies indicate cannabidiol works as a consummate multi-tasker to protect the eye from growing a plethora of leaky blood vessels, the hallmark of diabetic retinopathy, says Dr. Gregory I. Liou, molecular biologist at the Medical College of Georgia.”

http://www.sciencedaily.com/releases/2006/02/060227184647.htm

Anticoagulant effects of a Cannabis extract in an obese rat model.

“Blood coagulation studies were conducted to determine the possible anti-/prothrombotic effect of an organic cannabis extract and the three major cannabinoids, THC, CBD and CBN…

The study thus shows that Cannabis sativa and the cannabinoids, THC and CBN, display anticoagulant activity and may be useful in the treatment of diseases such as type 2 diabetes in which a hypercoagulable state exists.”

 http://www.ncbi.nlm.nih.gov/pubmed/16644197