Effect of anandamide in Plasmodium Berghei-infected mice.

“Eryptosis, the suicidal death of erythrocytes, is characterized by exposure of phosphatidylserine at the erythrocyte surface and cell shrinkage.

Triggers of eryptosis include anandamide.

Enhanced eryptosis of infected human erythrocytes is expected to delay the development of parasitaemia during infection with Plasmodium, the parasite causing malaria.

The present experiments aimed to test, whether anandamide influences eryptosis, parasite growth and/or host survival during in vitro or in vivo infection with Plasmodia.

In vivo administration of anandamide blunted the parasitaemia and significantly enhanced the survival of P. berghei-infected mice.

In conclusion, anandamide stimulated eryptosis of infected erythrocytes thus counteracting parasitaemia and a lethal course of the disease.”

http://www.ncbi.nlm.nih.gov/pubmed/20798520

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Cannabinoid receptor 2 modulates susceptibility to experimental cerebral malaria through a CCL17-dependent mechanism.

“Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain-barrier and a strong inflammation in the brain.

We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM).

Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2-/-) mice inoculated with Plasmodium berghei ANKA-erythrocytes exhibited enhanced survival and a diminished blood-brain-barrier disruption.

Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice.

Hematopoietic-derived immune cells were responsible for the enhanced protection in bone-marrow-chimeric (BM)-Cnr2-/- mice. Mixed BM-chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b+ cell population, containing macrophages and neutrophils, expanded in the Cnr2-/- spleen after infection and expressed macrophage mannose receptors, arginase-1 activity and IL-10.

Also in the Cnr2-/-brain CD11b+ cells that expressed selected anti-inflammatory markers accumulated and expression of inflammatory mediators IFN-γ and TNF-α was reduced.

Finally, the M2-macrophage chemokine CCL17 was identified as essential factor for enhanced survival in the absence of CB2, since CCL17 x Cnr2 double-deficient mice were fully susceptible to ECM.

Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.”

http://www.ncbi.nlm.nih.gov/pubmed/27474745

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“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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Minor oxygenated cannabinoids from high potency Cannabis sativa L.

“Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC-MS.

These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexa-hydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, Δ9-THC aldehyde A, 8-oxo-Δ9-THC, 10aα-hydroxy-10-oxo-Δ8-THC, 9α-hydroxy-10-oxo-Δ6a,10a-THC, and 1’S-hydroxycannabinol, respectively.

The latter compound showed moderate anti-MRSa (IC50 10.0μg/mL), moderate antileishmanial (IC50 14.0μg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50values of 3.4 and 2.3μg/mL, respectively.”

http://www.ncbi.nlm.nih.gov/pubmed/26093324

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Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of Cerebral Malaria.

“Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits.

Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties.

In the present work, we evaluated the effects of CBD in a murine model of CM…

Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.”

http://www.ncbi.nlm.nih.gov/pubmed/25595981

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

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Therapeutic potential of cannabinoid medicines.

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

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Marijuana first plants cultivated by man for medication (Update)

“Marijuana (Cannabis sativa L.) is one of the first plants cultivated by man. Shrouded in controversy, the intriguing history of cannabis as a medication dates back thousands of years before the era of Christianity.

Scientists believe the hemp plant originated in Asia. In 2737 B.C., Emperor Shen Neng of China prescribed tea brewed from marijuana leaves as a remedy for muscle injuries, rheumatism, gout, malaria, and memory loss. During the Bronze Age in 1400 B.C., cannabis was used throughout the eastern Mediterranean to ease the pain of childbirth and menstrual maladies.

More than 800 years before the birth of Christ, hemp was extensively cultivated in India for both its fiber and healing medicinal properties. William Brooke O’Shaughnessy, an Irish physician famous for his investigative research in pharmacology, is credited with introducing the therapeutic, healing properties of cannabis to Western medicine. During the 1830’s Dr. O’Shaughnessy, working for the British in India, conducted extensive experiments on lab animals. Encouraged by his results, Dr. O’Shaughnessy commenced patient treatment with marijuana for pain and muscle spasms. Further experiments indicated that marijuana was beneficial in the treatment of stomach cramps, migraine headaches, insomnia and nausea. Marijuana was also proven to be an effective anticonvulsant.

From the 1840s to the 1890s, hashish and marijuana extracts were among the most widely prescribed medications in the United States The 1850 United States Census records 8,327 marijuana plantations, each larger than 2000 acres. Recreational use of marijuana was not evident until early in the 20th century. Marijuana cigarettes became popular, introduced by migrants workers that brought marijuana with them from Mexico. With the onset of Prohibition, recreational use of marijuana skyrocketed. During the early 1930s, hash bars could be found all across the United States.

Although protested by the American Medical Association, the 1937 Marijuana Tax Act banned the cultivation and use of cannabis by federal law. Under the law, cultivation, distribution and consumption of cannabis products for medicinal, practical or recreational was criminalized and harsh penalties were implemented.”

More: http://guardianlv.com/2013/06/marijuana-first-plants-cultivated-by-man-for-medication/

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A Brief History of Medical Marijuana – TIME

“Should Professors Cheech and Chong ever receive university tenure teaching the medical history of their favorite subject, the course pack would be surprisingly thick.

As early as 2737 B.C., the mystical Emperor Shen Neng of China was prescribing marijuana tea for the treatment of gout, rheumatism, malaria and, oddly enough, poor memory. The drug’s popularity as a medicine spread throughout Asia, the Middle East and down the eastern coast of Africa, and certain Hindu sects in India used marijuana for religious purposes and stress relief. Ancient physicians prescribed marijuana for everything from pain relief to earache to childbirth…

By the late 18th century, early editions of American medical journals recommend hemp seeds and roots for the treatment of inflamed skin, incontinence and venereal disease. Irish doctor William O’Shaughnessy first popularized marijuana’s medical use in England and America. As a physician with the British East India Company, he found marijuana eased the pain of rheumatism and was helpful against discomfort and nausea in cases of rabies, cholera and tetanus.”

More: http://www.time.com/time/health/article/0,8599,1931247,00.html

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The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

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From cannabis to the endocannabinoid system: refocussing attention on potential clinical benefits.

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“Cannabis sativa is one of the oldest herbal remedies known to man. Over the past four thousand years, it has been used for the treatment of numerous diseases but due to its psychoactive properties, its current medicinal usage is highly restricted. In this review, we seek to highlight advances made over the last forty years in the understanding of the mechanisms responsible for the effects of cannabis on the human body and how these can potentially be utilized in clinical practice. During this time, the primary active ingredients in cannabis have been isolated, specific cannabinoid receptors have been discovered and at least five endogenous cannabinoid neurotransmitters (endocannabinoids) have been identified. Together, these form the framework of a complex endocannabinoid signalling system that has widespread distribution in the body and plays a role in regulating numerous physiological processes within the body. Cannabinoid ligands are therefore thought to display considerable therapeutic potential and the drive to develop compounds that can be targeted to specific neuronal systems at low enough doses so as to eliminate cognitive side effects remains the ‘holy grail’ of endocannabinoid research.”

http://www.ncbi.nlm.nih.gov/pubmed/23155985

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