The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ9-tetrahydrocannabinol acting through CB1 receptors.

Posted on November 23, 2015 by David

“Sativex®, an equimolecular combination of Δ9-tetrahydrocannabinol-botanical drug substance (Δ9-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain.

However, further evidence suggest that it could be also active as disease-modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components.

In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice.

We compared the effect of a Sativex-like combination of Δ9-THC-BDS (10mg/kg) and CBD-BDS (10mg/kg) with Δ9-THC-BDS (20mg/kg) or CBD-BDS (20mg/kg) administered separately by intraperitoneal administration to EAE mice.

Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease.

The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS.

These effects were completely reproduced by the treatment with Δ9-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord.

Next, we investigated the potential targets involved in the effects of Δ9-THC-BDS by selectively blocking CB1 or PPAR-γ receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB1 receptor antagonist.

Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Δ9-THC-BDS acting through CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26590655

HU-446 and HU-465, derivatives of the non-psychoactive cannabinoid cannabidiol, decrease the activation of encephalitogenic T cells.

Posted on August 12, 2015 by David

“Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS).

Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihydro-7-hydroxy-CBD; HU-446) and of synthetic (+)-CBD ((+)-8,9-dihydro-7-hydroxy-CBD; HU-465)…

These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases. ”

http://www.ncbi.nlm.nih.gov/pubmed/26259697

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis.

Posted on July 22, 2015 by David

“Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system.

Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS)…

These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26189763

Activation of Cannabinoid CB2 receptors Reduces Hyperalgesia in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis.

Posted on April 8, 2015 by David

“Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis…

Our results suggest that JWH-133 acts at CB2 receptors, most likely within the dorsal horn of the spinal cord, to suppress the hypersensitivity associated with experimental autoimmune encephalomyelitis.

These are the first pre-clinical studies to directly promote CB2 as a promising target for the treatment of central pain in an animal model of multiple sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/25849525

Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells.

Posted on March 18, 2015 by David

“Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and IL-17 secretion. However, the mechanisms of CBD anti-inflammatory activities are unclear…

Our data suggests that CBD exerts its immunoregulatory effects via induction of CD4(+)CD25(-)CD69(+)LAG3(+) cells in MOG35-55-activated APC/TMOG co-cultures. This is accompanied by EGR2-dependent anergy of stimulated TMOG cells as well as a switch in their intracellular STAT3/STAT5 activation balance leading to the previously observed decrease in Th17 activity.”

http://www.ncbi.nlm.nih.gov/pubmed/25779454

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

Posted on December 30, 2014 by David

“Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system.

Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms.

However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease.

… we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability.

Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels.

In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans…

… demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo.

Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.”

http://www.ncbi.nlm.nih.gov/pubmed/25537576

http://www.thctotalhealthcare.com/category/experimental-autoimmune-encephalomyelitis/

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

Targeting the CB2 receptor for immune modulation.

Posted on June 9, 2014 by David

“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

Cannabinoid Modulation of Neuroinflammatory Disorders

Posted on June 9, 2014 by David

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/

Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells.

Posted on June 9, 2014 by David

“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

CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies

Posted on June 9, 2014 by David

“Amongst the various demyelinating diseases that affect the central nervous system, those induced by an inflammatory response stand out because of their epidemiological relevance. The best known inflammatory-induced demyelinating disease is multiple sclerosis, but the immune response is a common pathogenic mechanism in many other less common pathologies (e.g., acute disseminated encephalomyelitis and acute necrotizing haemorrhagic encephalomyelitis).

In all such cases, modulation of the immune response seems to be a logical therapeutic approach.

Cannabinoids are well known immunomodulatory molecules that act through CB1 and CB2 receptors. While activation of CB1 receptors has a psychotropic effect, activation of CB2 receptors alone does not. Therefore, to bypass the ethical problems that could result from the treatment of inflammation with psychotropic molecules, considerable effort is being made to study the potential therapeutic value of activating CB2 receptors.

In this review we examine the current knowledge and understanding of the utility of cannabinoids as therapeutic molecules for inflammatory-mediated demyelinating pathologies. Moreover, we discuss how CB2 receptor activation is related to the modulation of immunopathogenic states.

The activation of CB2receptors results in the modulation of the inflammatory response, restraining one of the agents responsible for the progress of demyelination and neuronal death, the ultimate causes of the symptoms in pathologies such as MS and EAE.

The modulation of inflammatory molecules through CB2 receptors could also enhance remyelination, stimulating the survival of oligodendrocyte precursors and neural stem/precursor cells, and their development into mature oligodendrocytes.

…this raises the possibility that CB2 agonists could have the potential to promote brain repair.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219542/#!po=48.0769