Author Archives: David Worrell

The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.

Posted on by

“One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.”

http://www.ncbi.nlm.nih.gov/pubmed/16616335

“Marijuana has been used in medicine for many centuries, and nowadays there is a renaissance in the study of the therapeutic effects of cannabinoids. One of the most active areas of research in the cannabinoid field is the study of the potential antitumoral application of these drugs. Our results unravel the mechanism of cannabinoid antitumoral action by demonstrating the proapoptotic role of the stress protein p8 via its downstream targets ATF-4, CHOP, and TRB3.

The identification of this pathway may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of potential antitumoral therapies with cannabinoids.

Our results also support that cannabinoid treatment does not activate this pathway in nontransformed cells, in line with the belief that cannabinoid proapoptotic action is selective for tumor versus nontumor cells, and that cannabinoids act in a synergic fashion with ER stress inducers as well as with other antitumoral agents.

The identification of the p8-regulated pathway described here may contribute to the design of therapeutic strategies for inhibiting tumor growth. In particular, our findings can help to improve the efficiency and selectivity of a potential cannabinoid-based antitumoral therapy.”

http://www.sciencedirect.com/science/article/pii/S1535610806000857

The complete chloroplast genomes of Cannabis sativa and Humulus lupulus.

Posted on by

“Cannabis and Humulus are sister genera comprising the entirety of the Cannabaceae sensu stricto, including C. sativa L. (marijuana, hemp), and H. lupulus L. (hops) as two economically important crops.

These two plants have been used by humans for many purposes including as a fiber, food, medicine, or inebriant in the case of C. sativa, and as a flavoring component in beer brewing in the case of H. lupulus.

In this study, we report the complete chloroplast genomes for two distinct hemp varieties of C. sativa, Italian “Carmagnola” and Russian “Dagestani”, and one Czech variety of H. lupulus “Saazer”.

Both C. sativa genomes are 153 871 bp in length, while the H. lupulus genome is 153 751 bp. The genomes from the two C. sativa varieties differ in 16 single nucleotide polymorphisms (SNPs), while the H. lupulus genome differs in 1722 SNPs from both C. sativa cultivars.”

http://www.ncbi.nlm.nih.gov/pubmed/26329384

Clinical perspectives on medical marijuana (cannabis) for neurologic disorders.

Posted on by

“The American Academy of Neurology published an evidence-based systematic review of randomized controlled trials using marijuana (Cannabis sativa) or cannabinoids in neurologic disorders.

Several cannabinoids showed effectiveness or probable effectiveness for spasticity, central pain, and painful spasms in multiple sclerosis.

The review justifies insurance coverage for dronabinol and nabilone for these indications.

Many insurance companies already cover these medications for other indications.

It is unlikely that the review will alter coverage for herbal marijuana.

Currently, no payers cover the costs of herbal medical marijuana because it is illegal under federal law and in most states.

Cannabinoid preparations currently available by prescription may have a role in other neurologic conditions, but quality scientific evidence is lacking at this time.”

http://www.ncbi.nlm.nih.gov/pubmed/26336632

Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence.

Posted on by

“Cannabinoid compounds include phytocannabinoids, endocannabinoids, and synthetics.

The two primary phytocannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), with CB1 receptors in the brain and peripheral tissue and CB2 receptors in the immune and hematopoietic systems.

The route of delivery of cannabis is important as the bioavailability and metabolism are very different for smoking versus oral/sublingual routes.

Gold standard clinical trials are limited; however, some studies have thus far shown evidence to support the use of cannabinoids for some cancer, neuropathic, spasticity, acute pain, and chronic pain conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/26325482

Fatty acids, endocannabinoids and inflammation.

Posted on by

“From their phylogenetic and pharmacological classification it might be inferred that cannabinoid receptors and their endogenous ligands constitute a rather specialised and biologically distinct signalling system.

However, the opposite is true and accumulating data underline how much the endocannabinoid system is intertwined with other lipid and non-lipid signalling systems.

Endocannabinoids per se have many structural congeners, and these molecules exist in dynamic equilibria with different other lipid-derived mediators, including eicosanoids and prostamides.

With multiple crossroads and shared targets, this creates a versatile system involved in fine-tuning different physiological and metabolic processes, including inflammation.

A key feature of this ‘expanded’ endocannabinoid system, or ‘endocannabinoidome’, is its subtle orchestration based on interactions between a relatively small number of receptors and multiple ligands with different but partly overlapping activities.

Following an update on the role of the ‘endocannabinoidome’ in inflammatory processes, this review continues with possible targets for intervention at the level of receptors or enzymes involved in formation or breakdown of endocannabinoids and their congeners.

Although its pleiotropic character poses scientific challenges, the ‘expanded’ endocannabinoid system offers several opportunities for prevention and therapy of chronic diseases.

In this respect, successes are more likely to come from ‘multiple-target’ than from ‘single-target’ strategies.”

http://www.ncbi.nlm.nih.gov/pubmed/26325095

Endocannabinoid System Contributes to Liver Injury and Inflammation by Activation of Bone Marrow-Derived Monocytes/Macrophages in a CB1-Dependent Manner.

Posted on by

“Hepatic injury undergoes significant increases in endocannabinoids and infiltrations of macrophages, yet the concrete mechanisms of changes in endocannabinoids and the functions of macrophage-expressed cannabinoid receptors (CBs) are unclear…

In the chimeric murine model, we found that blockade of CB1 by administration of a CB1 antagonist inhibited the recruitment of Bone marrow-derived monocytes/macrophages (BMM) into injured liver using immunofluorescence staining and FACS, but it did not have effects on migration of T cells and dendritic cells without CB1 expression. Furthermore, activation of CB1 enhanced cytokine expression of BMM. In vivo, inhibition of CB1 attenuated the inflammatory cytokine level through real-time RT-PCR and cytometric bead array, ameliorating hepatic inflammation and fibrosis.

In this study, we identify inactivation of BMM-expressed CB1 as a therapeutic strategy for reducing hepatic inflammation and fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/26320250

Medical Marijuana: Reducing Spasticity in Multiple Sclerosis Patients

Posted on by

 

“Medical marijuana is a justifiable treatment for spasticity in patients with MS.

Interviews indicate that many patients choose marijuana over other medicines because they experience minimal side effects and rapid improvements in motor functioning…

Compared to the steroids, tranquilizers, and sedatives usually prescribed for MS patients, marijuana is remarkably safe and benign…

There is a lack of evidence for long-term risks associated with marijuana use. The short-term risks are minimal and short-lived.

Studies verify the positive relationship between medical marijuana use and reduced spasticity.

Voters are realizing the cruelty associated with robbing a terminally or chronically ill patient from the medicine that most relieves their pain.

MS is a chronic disease that can lead to severe pain and disability if untreated. For these reasons, medical marijuana should be available to patients who understand the risks associated with its use.

Until medical research develops an equally effective oral drug, marijuana will remain a reasonable option for patients suffering from MS.”

http://www.vanderbilt.edu/AnS/psychology/health_psychology/medicalmarijuana.htm

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

Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease.

Posted on by

“Parkinson’s disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain.

Symptomatic therapies are available but no treatment slows or prevents the loss of neurons.

Neuroinflammation has been implicated in its pathogenesis.

To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients.

Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated.

The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death.

Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects.

Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits.

The results expand the current understanding of the role that this signalling system has and its potential influence in PD.”

Age-related changes in the endocannabinoid system in the mouse hippocampus.

Posted on by

“Previous studies have demonstrated that the endocannabinoid system significantly influences the progression of brain ageing, and the hippocampus is one of the brain regions most vulnerable to ageing and neurodegeneration.

We have further examined age-related changes in the hippocampalendocannabinoid system by measuring the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in young and old mice from two different mouse strains.

We found a decrease in 2-AG but not AEA levels in aged mice.

In order to identify the cause for 2-AG level changes, we investigated the levels of several enzymes that contribute to synthesis and degradation of 2-AG in the hippocampus.

We found a selective decrease in DAGLα mRNA and protein levels as well as an elevated MAGL activity during ageing.

We hypothesize that the observed decrease of 2-AG levels is probably caused by changes in DAGLα expression and MAGL activity.

This finding can contribute to the existing knowledge about the processes underlying selective vulnerability of the hippocampus to ageing and age-related neurodegeneration.”

http://www.ncbi.nlm.nih.gov/pubmed/26278494

Effect of anandamide on endometrial adenocarcinoma (Ishikawa) cell numbers: implications for endometrial cancer therapy.

Posted on by

The Lancet logo

“We have previously shown that patients with endometrial carcinoma express elevated concentrations of the endocannabinoid, anandamide (AEA), in both their plasma and their endometrial tissue and that the endometrial carcinoma cell line, Ishikawa, contains the receptors to which AEA binds.

Several studies have reported that human and rodent cancer cell lines die in response to high AEA concentrations.

The incidence of endometrial carcinoma continues to escalate and, although surgical treatment has improved, morbidity and mortality rates have not. A move towards a novel non-surgical therapeutic option is thus required, and the endocannabinoid system provides a good candidate target.

We aimed to investigate the effects of AEA on the survival and proliferation of an endometrial carcinoma cell model.

Our results show that AEA induces a decrease in Ishikawa cell number probably through inhibition of cell proliferation rather than cell death.

These data suggest that the increased plasma and tissue AEA concentrations observed in patients with endometrial cancer is a counter mechanism against further cancer growth and points to the endocannabinoid system as a potentially new therapeutic target.”

http://www.ncbi.nlm.nih.gov/pubmed/26312842

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60335-X/fulltext