Cannabis Counter Brain Cell Damage After a Stroke

“New research by University of Otago scientists suggests some mechanisms in the brain targeted by cannabis could become drugs targets to counter brain cell damage after a stroke.

Researchers from the Medical School’s Department of Pharmacology and Toxicology have been the first in the world to show the cannabinoid CB2 receptor appears in the rat brain following a stroke.

Their findings were published recently in the journal Neuroscience Letters.

Dr John Ashton says the CB2 receptor is a protein produced as part of the body’s immune response system.

“This response is triggered by stroke and causes the inflammation that leads to damage in the area of the brain around where the stroke has occurred.

“If the inflammation can be stopped or reduced then it offers the hope of reducing the extent of the damage caused by stroke – and CB2 offers a potential target for such a drug.”

Dr Ashton says cannabis targets both the CB2 and the related CB1 receptors.

“THC, the major active ingredient of cannabis, acts mainly on CB1 but it also affects CB2. While THC is known to have some positive effects in terms of pain management its use is severely limited because of the way it triggers the psychoactive CB1 receptors in the brain,” he says.

“The aim would be to develop a drug that targets the CB2 receptor without affecting CB1.”

Dr Ashton says the relationship between cannabis and cannabinoid drugs has similarities to the relationship between heroin and codeine.

“Heroin and codeine share common targets, but by designing codeine in such a way that it eliminated the psychoactive side-effects seen with heroin, a therapeutically useful drug was developed. There is the potential to do the same with cannabinoids.”

Drugs targeting CB2 could also have potential therapeutic use in other conditions involving inflammatory damage to the brain, such as Huntington’s Disease and Alzheimer’s Disease. There may also be scope to use them in pain management.

“CB2 cells are also found in the spinal cord. They regulate pain signals making them a potential target for new pain killing drugs.””

http://www.hightimes.com/read/cannabis-counter-brain-cell-damage-after-stroke

Long-term cannabinoid type 2 receptor agonist therapy decreases Bacterial Translocation In Rats with cirrhosis and ascites.

“Intestinal hyper-permeability, impaired peritoneal macrophages (PMs) phagocytosis, and, bacterial translocation (BT) resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP), together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications.

Manipulation of cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokines release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats…

CONCLUSIONS:

Our study suggests that CB2R agonist have the potential to treat BT and various relevant abnormalities through the inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα releases in cirrhosis. Overall, chronic CB2R agonist treatment affects multiple approach mechanisms, and the direct effect on hyperdynamic circulation is only minor.”

http://www.ncbi.nlm.nih.gov/pubmed/24953022

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling.

“The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells.

Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo.

These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.”

http://www.ncbi.nlm.nih.gov/pubmed/24942731

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

Cannabinoid CB2 Receptor as a New Phototherapy Target for the Inhibition of Tumor Growth.

“The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment…

Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment.”

http://www.ncbi.nlm.nih.gov/pubmed/24779700

“Target-selective phototherapy using a ligand-based photosensitizer for type 2 cannabinoid receptor. Phototherapy is a powerful, noninvasive approach for cancer treatment, with several agents currently in clinical use… We show that our CB2R-targeted phototherapy agent, IR700DX-mbc94, is specific for CB2R and effective only when bound to the target receptor. Overall, this opens up the opportunity for development of an alternative treatment option for CB2R-positive cancers.”  http://www.ncbi.nlm.nih.gov/pubmed/24583052

Antagonism of cannabinoid receptor 2 pathway suppresses IL-6-induced immunoglobulin IgM secretion.

“Cannabinoid receptor 2 (CB2) is expressed predominantly in the immune system, particularly in plasma cells, raising the possibility that targeting the CB2 pathway could yield an immunomodulatory effect.

Although the role of CB2 in mediating immunoglobulin class switching has been reported, the effects of targeting the CB2 pathway on immunoglobulin secretion per se remain unclear…

These results uncover a novel function of CB2 antagonists and suggest that CB2 ligands may be potential modulators of immunoglobulin secretion.”

Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders.

Publication cover image

“Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the “immunocannabinoid” system. This system can be an important signaling pathway for immune modulation.

To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation.

Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity.

The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses”

https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0205111

https://www.ncbi.nlm.nih.gov/pubmed/15845647

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

“The cannabinoid system consists of cannabinoid receptors and their ligands, including endocannabinoids, synthetic cannabinoid receptor agonists and antagonists, and phytocannabinoids.

Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators.

…cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis.

Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs.

Because of their anti-inflammatory functions targeting various immune cells, CB2R agonists could represent valuable therapeutic agents for the treatment of chronic inflammatory conditions.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488886/

Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation.

Figure 2

“The cannabinoids are a group of terpenophenolic compounds present in the marijuana plant, Cannabis sativa. At present, three general types of cannabinoids have been identified: phytocannabinoids present uniquely in the cannabis plant, endogenous cannabinoids produced in humans and animals, and synthetic cannabinoids generated in a laboratory. It is worth noting that Cannabis sativa produces over 80 cannabinoids…

An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions.

…there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer’sdisease to name a few), mainly mediated by CB(2) activation.

This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.

The full potential of CB2 agonists as therapeutic agents remains to be realized.

Despite some inadequacies of preclinical models to predict clinical efficacy in humans and differences between the signaling of human and rodent CB2 receptors, the development of selective CB2 agonists may open new avenues in therapeutic intervention.

Such interventions would aim at reducing the release of pro-inflammatory mediators particularly in chronic neuropathologic conditions such as HAND or MS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663904/

 

Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis.

Figure 1

“Our aim was to evaluate the roles of the cannabinoid pathway in the induction and propagation of systemic sclerosis (SSc) in a mouse model…

Experiments performed in CB2-deficient mice confirmed the influence of CB2 in the development of systemic fibrosis and autoimmunity. Therefore, we demonstrate that the CB2 receptor is a potential target for the treatment of SSc because it controls both skin fibroblast proliferation and the autoimmune reaction.

In this report, we demonstrate for the first time the highly protective role of cannabinoid agonists in SSc. Because these agonists are available and well-tolerated under clinical conditions, our data offer a new therapeutic opportunity in this life-threatening disease.

In conclusion, modulation of the endocannabinoid system is a novel approach for the treatment of various inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893662/

Targeting the CB2 receptor for immune modulation.

“Early work on the biology of the components of Cannabis sativa showed evidence for a potential influence on immune regulation.

With the discovery of a peripheral cannabinoid receptor associated with immune cells, many laboratories have sought to link the immunoregulatory activities of cannabinoid compounds with this receptor, hoping that such compounds would lack the psychoactive effects of marijuana and other nonspecific cannabinoid agonists.

In this report, the authors investigate the role of the cannabinoid CB2 receptor in immune regulation, with particular emphasis on compounds shown to regulate immune cell recruitment.

The authors conclude by using the immune cell recruitment model to rationalise cannabinoidCB2 receptor-specific effects in modulating immune disease, particularly the increasing evidence for its role in experimental autoimmuneencephalomyelitis and in influencing bone density.”

http://www.ncbi.nlm.nih.gov/pubmed/16981823