Tag Archives: cannabinoid

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

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“Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis…

This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases.

Cannabidiol (CBD) is a major non-psychoactive cannabinoid component of marijuana.

Together, these studies not only demonstrate that CBD can protect the host from acute liver injury but also provide evidence for the first time that MDSCs may play a critical role in protecting the liver from acute inflammation.

Non-psychoactive cannabinoids such as CBD possess great therapeutic potential in treating various inflammatory liver diseases, including autoimmune hepatitis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069975/

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

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“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/

Cannabinoid Receptor Type 1- and 2-mediated Increase in Cyclic AMP Inhibits T Cell Receptor-triggered Signaling

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FIGURE 1.

“The aim of this study was to characterize inhibitory mechanisms on T cell receptor signaling mediated by the cannabinoid receptors CB1 and CB2. Both receptors are coupled to G(i/o) proteins, which are associated with inhibition of cyclic AMP formation…

These findings help to better understand the immunosuppressive effects of cannabinoids and explain the beneficial effects of these drugs in the treatment of T cell-mediated autoimmune disorders like multiple sclerosis.

To sum up, our results help to explain immunosuppressive effect of cannabinoid drugs, which may be important for the pharmacological evaluation of these drugs, e.g. with respect to their use in neuroinflammatory diseases and T cell-mediated autoimmune disorders like multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790974/#!po=45.6522

Targeting the CB2 receptor for immune modulation.

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“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

Updating the chemistry and biology of cannabinoid CB2 receptor-specific inverse agonists.

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“The cannabinoid CB(2) receptor continues to be an intriguing target for the potential therapeutic benefit of cannabinoids. Because this receptor is significantly found outside the brain, compounds specific for the CB(2) receptor may be free of the side effects that have plagued cannabinoid CB(1) receptor-based therapeutics.

In this review, we will discuss a class of compounds which modulate the constitutive activity of the cannabinoid CB(2) receptor, the inverse agonists. We will discuss recent chemical advances that provide new compounds to investigate the biology based on this pharmacology. We will then discuss new biology associated with the cannabinoid CB(2) receptor for hints of how these compounds can best be utilized in vivo.”

http://www.ncbi.nlm.nih.gov/pubmed/20370714

Cannabinoid Modulation of Neuroinflammatory Disorders

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Table 1.

“Cannabis sativa is a herb belonging to the Cannabaceae family, characterized by palmate leaves and numerous fibers. Its first record as a medicine dates back to 5000 years ago and it was found in China, where cannabis was used for a myriad of purposes and diseases, including malaria, neuropathic pain, nausea, sexual dysfunction and constipation.

The use of cannabis spread from Central Asia and deeply influenced Indian folk medicine. However, sedative and psychotropic effects of cannabis turned it into a recreational drug. This fact resulted in discrimination against the consumption of the cannabis plant and its derivatives, which delayed the scientific findings in this field…

In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ(9)-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses.

In this context, cannabinoids have been studied for their possible therapeutic properties in neuroinflammatory diseases. In this review, historic and biochemical aspects of cannabinoids are discussed, as well as their function as modulators of inflammatory processes and therapeutic perspectives for neurodegenerative disorders, particularly, multiple sclerosis.

Cannabinoid compounds may be extracted from the plant (phytocannabinoids) or be artificially obtained (synthetic cannabinoids)…

To date, it is still impossible to prove or rule out all benefits of cannabis described empirically by ancient herbal practitioners. For now, science aims to understand how cannabinoid compounds are associated with neuroinflammation and how cannabis-based medicine can help millions of patients worldwide.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386505/

Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation.

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<br /> FIGURE 1.<br />

“Cannabinoids are compounds derived from the Cannabis sativa (marijuana) plant, as well as produced endogenously in the brain and by immune cells. Cannabinoids mediate their effect through cannabinoid receptors (CB), designated CB1 and CB2, which belong to a superfamily of G-protein-coupled receptors.

CB1 receptors are expressed at high levels in CNS, where they regulate psychoactivity. CB1 receptors are also expressed on immune cells. In contrast, the CB2 receptors are primarily expressed on immune cells and do not contribute to the psychoactivity. The presence of endogenous CB-ligand systems in immune cells suggests that they may play a critical physiological role, the precise nature of which remains to be characterized.

Cannabinoids can decrease the immune response… Cannabinoids have also been widely used in the treatment of pain and inflammation.

Moreover, preliminary studies have shown the possible use of cannabinoids in the treatment of autoimmune diseases such as multiple sclerosis.

Recent studies from our lab demonstrated that Δ9-tetrahydrocannabinol (THC) can trigger apoptosis in vivo in thymocytes and splenocytes, which may account for immunosuppression.

 We demonstrate for the first time that THC and endocannabinoids such as anandamide can induce apoptosis in DCs through activation of CB1 and CB2 receptors.

These studies provide the basis for understanding the mechanism by which THC triggers immunosuppression and mediates anti-inflammatory properties.

Many studies have suggested the use of THC or related cannabinoids in the treatment of autoimmune diseases.”

http://www.jimmunol.org/content/173/4/2373.long

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

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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/

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

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“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

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/