Evaluation of Marijuana Compounds on Neuroimmune Endpoints in Experimental Autoimmune Encephalomyelitis.

Current Protocols in Toxicology

“Cannabinoid compounds refer to a group of more than 60 plant-derived compounds in Cannabis sativa, more commonly known as marijuana. Exposure to marijuana and cannabinoid compounds has been increasing due to increased societal acceptance for both recreational and possible medical use. Cannabinoid compounds suppress immune function, and while this could compromise one’s ability to fight infections, immune suppression is the desired effect for therapies for autoimmune diseases. It is critical, therefore, to understand the effects and mechanisms by which cannabinoid compounds alter immune function, especially immune responses induced in autoimmune disease. Therefore, this unit will describe induction and assessment of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and its potential alteration by cannabinoid compounds. The unit includes three approaches to induce EAE, two of which provide correlations to two forms of MS, and the third specifically addresses the role of autoreactive T cells in EAE.”

https://www.ncbi.nlm.nih.gov/pubmed/29512125

http://onlinelibrary.wiley.com/doi/10.1002/cptx.43/abstract

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The inhibition of CB1 receptor accelerates the onset and development of EAE possibly by regulating microglia/macrophages polarization.

Journal of Neuroimmunology

“Cannabinoid 1 receptor (CB1R) regulates the neuro-inflammatory and neurodegenerative damages of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R inhibition exerts inflammatory effects is still unclear. Here, we explored the cellular and molecular mechanisms of CB1R in the treatment of EAE by using a specific and selective CB1R antagonist SR141716A. Our study demonstrated that SR141716A accelerated the clinical onset and development of EAE, accompanied by body weight loss. SR141716A significantly up-regulated the expression of toll like receptor-4 (TLR-4) and nuclear factor-kappaB/p65 (NF-κB/p65) on microglia/macrophages of EAE mice as well as levels of inflammatory factors (TNF-α, IL-1β, IL-6) and chemokines (MCP-1, CX3CL1), accompanied by the shifts of cytokines from Th2 (IL-4, IL-10) to Th1 (IFN-γ)/Th17 (IL-17) in the spinal cords of EAE mice. Similar changes happened on splenic mononuclear cells (MNCs) except chemokine CX3CL1. Consistently, SR141716A promoted BV-2 microglia to release inflammatory factors (TNF-α, IL-1β, IL-6) while inhibited the production of IL-10 and chemokines (MCP-1, CX3CL1). Furthermore, when splenic CD4+ T cells co-cultured with SR141716A-administered BV-2 microglia, the levels of IL-4 and IL-10 were decreased while production of IL-17 and IFN-γ increased significantly. Our research indicated that inhibition of CB1R induced M1 phenotype-Th17 axis changed of microglia/macrophages through TLR-4 and NF-κB/p65 which accelerated the onset and development of EAE. Therefore, CB1R may be a promising target for the treatment of MS/EAE, but its complexity remains to be carefully considered and studied in further clinical application.”

https://www.ncbi.nlm.nih.gov/pubmed/29501084

http://www.jni-journal.com/article/S0165-5728(17)30467-8/fulltext

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Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice.

British Journal of Pharmacology

“Cannabis extracts and several cannabinoids have been shown to exert broad anti-inflammatory activities in experimental models of inflammatory CNS degenerative diseases.

Clinical use of many cannabinoids is limited by their psychotropic effects. However, phytocannabinoids like cannabidiol (CBD), devoid of psychoactive activity, are, potentially, safe and effective alternatives for alleviating neuroinflammation and neurodegeneration.

Treatment with CBD during disease onset ameliorated the severity of the clinical signs of EAE.

CBD, a non-psychoactive cannabinoid, ameliorates clinical signs of EAE in mice, immunized against MOG. Suppression of microglial activity and T-cell proliferation by CBD appeared to contribute to these beneficial effects.”

https://www.ncbi.nlm.nih.gov/pubmed/21449980

“In summary, we have shown that CBD administered to MOG-immunized C57BL/6 mice, at the onset of EAE disease, reduced the severity of the clinical signs of EAE. CBD treatment was accompanied by diminished axonal loss and inflammation (infiltration of T cells and microglial activation). Moreover, CBD prevented proliferation of myelin-specific T cells in vitro. These observations suggest that CBD may have potential for alleviating MS-like pathology.” http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01379.x/full

“Study Shows Cannabidiol (CBD) Improves MS-Like Symptoms”  http://www.prohealth.com/library/showarticle.cfm?libid=31211

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Managing neuropathic pain in multiple sclerosis: Pharmacological interventions.

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“Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of the plethora of motor and sensory disturbances experienced by sufferers, neuropathic pain is a highly prevalent and debilitating symptom, and at present remains extremely difficult to treat. Common forms of neuropathic pain seen in MS patients include central neuropathic pain, Lhermitte’s phenomenon and trigeminal neuralgia, which are all speculated to arise from specific patterns of lesion formation.

OBJECTIVE:

Efficacious pharmacological interventions for the treatment of neuropathic pain associated with MS are lacking, and have been largely informed by drug trials in peripheral neuropathies and spinal cord injury.

METHOD/RESULTS:

Neuropathic pain in MS is inadequately relieved by conventional analgesics, and first-line therapies are generally comprised of anti-depressive and anti-convulsive drugs. A range of alternatives have been proposed and tested with variable success, including cannabinoids and certain opioid analgesics. Animals with experimental autoimmune encephalomyelitis (EAE), an autoimmune model of MS, also exhibit neuropathic pain symptoms.

CONCLUSION:

Studies aimed at understanding the mechanisms underlying EAE-induced neuropathic pain and investigating the efficacy of novel pharmacological interventions at the animal level offer an exciting area of future research, and may inform future therapeutic options for MS-associated neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28875858

 

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Mechanisms of action of cannabidiol in adoptively transferred experimental autoimmune encephalomyelitis.

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“Cannabidiol (CBD) is one of the most important compounds in Cannabis sativa, lacks psychotropic effects, and possesses a high number of therapeutic properties including the amelioration of experimental autoimmune encephalomyelitis (EAE).

The aim of this study was to analyse the relative efficacy of CBD in adoptively transferred EAE (at-EAE), a model that allows better delineation of the effector phase of EAE.

Preventive intraperitoneal treatment with CBD ameliorated the clinical signs of at-EAE. CBD markedly improved the clinical signs of at-EAE and reduced infiltration, demyelination and axonal damage. The CBD-mediated decrease in the viability of encephalitogenic cells involves ROS generation, apoptosis and a decrease in IL-6 production and may contribute to the therapeutic effect of this compound.”

https://www.ncbi.nlm.nih.gov/pubmed/28867485

http://www.sciencedirect.com/science/article/pii/S0014488617302212

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Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with In Vivo Efficacy in a Mouse Model of Multiple Sclerosis.

Journal of Medicinal Chemistry

“Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor.

We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor.

Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.”

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(-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis.

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“(-)-β-caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has already been shown in precedent literature to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain.

Herein, we endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). Furthermore, we sought to demonstrate some of the mechanisms that underlie the modulation BCP exerts on autoimmune activated T cells, the pro-inflammatory scenery of the central nervous system (CNS), and demyelination.

Our findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE. In addition, data hereby presented indicates that mechanisms underlying BCP immunomodulatory effect seems to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor.

Altogether, our study represents significant implications for clinical research and strongly supports the effectiveness of BCP as a novel molecule to target in the development of effective therapeutic agents for MS.” https://www.ncbi.nlm.nih.gov/pubmed/28368293

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Interaction between interleukin-1β and type-1 cannabinoid receptor is involved in anxiety-like behavior in experimental autoimmune encephalomyelitis.

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“Mood disorders, including anxiety and depression, are frequently diagnosed in multiple sclerosis (MS) patients, even independently of the disabling symptoms associated with the disease.

Anatomical, biochemical, and pharmacological evidence indicates that type-1 cannabinoid receptor (CB1R) is implicated in the control of emotional behavior and is modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE).

We investigated whether CB1R could exert a role in anxiety-like behavior in mice with EAE. We performed behavioral, pharmacological, and electrophysiological experiments to explore the link between central inflammation, mood, and CB1R function in EAE.

Overall, results of the present investigation indicate that synaptic dysfunction linked to CB1R is involved in EAE-related anxiety and motivation-based behavior and contribute to clarify the complex neurobiological mechanisms underlying mood disorders associated to MS.

Collectively, our data contribute to clarify the synaptic and, at least in part, molecular basis of mood disturbances in EAE and, possibly, MS. Understanding the neurobiological underpinning of anxiety-like behavior in EAE mice is of crucial importance to optimize the treatment of mood disturbance in MS and, possibly, other neuroinflammatory diseases.

In this direction, targeting the endocannabinoid system may be a valid therapeutic tool for the treatment of both psychiatric and motor symptoms in MS patients.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009553/

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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A Sativex(®) -like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

“Sativex(®) is an oromucosal spray, containing equivalent amounts of Δ(9) -tetrahydrocannabinol (Δ(9) -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS).

In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler’s murine encephalomyelitis virus-induced demyelinating disease model of MS.

The data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair.”

http://www.ncbi.nlm.nih.gov/pubmed/25857324

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