Tag Archives: Cannabinoids

Modulation of cellular redox homeostasis by the endocannabinoid system

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“The endocannabinoid system (ECS) and reactive oxygen species (ROS) constitute two key cellular signalling systems that participate in the modulation of diverse cellular functions.

Importantly, growing evidence suggests that cross-talk between these two prominent signalling systems acts to modulate functionality of the ECS as well as redox homeostasis in different cell types…

To conclude, there is growing appreciation that the ECS may play an important role in the regulation of cellular redox homeostasis…

Indeed, the studies highlighted in this review show that ECS function can impact upon free radical production in a number of different ways.

Crucially, given the importance of redox status in the development of numerous pathologies, these findings identify ECS components as potential therapeutic targets for the treatment of oxidative stress-related neurological, cardiovascular and metabolic disorders.”

http://rsob.royalsocietypublishing.org/content/6/4/150276

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview.

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“The word dementia describes a class of heterogeneous diseases which etiopathogenetic mechanisms are not well understood. There are different types of dementia, among which, Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the more common.

Currently approved pharmacological treatments for most forms of dementia seem to act only on symptoms without having profound disease-modifying effects. Thus, alternative strategies capable of preventing the progressive loss of specific neuronal populations are urgently required.

In particular, the attention of researchers has been focused on phytochemical compounds that have shown antioxidative, anti-amyloidogenic, anti-inflammatory and anti-apoptotic properties and that could represent important resources in the discovery of drug candidates against dementia.

In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia.

We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.”

http://www.ncbi.nlm.nih.gov/pubmed/27110749

Advances towards the Discovery of GPR55 Ligands.

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“The G-protein-coupled receptor 55 (GPR55) was identified in 1999.

It was proposed as a novel member of the endocannabinoid system due to the fact that some endogenous, plant-derived and synthetic cannabinoid ligands act on GPR55. However, the complexity of the cellular downstream signaling pathways related to GPR55 activation delayed the discovery of selective GPR55 ligands.

It was only a few years ago that the high throughput screening of libraries of pharmaceutical companies and governmental organizations allowed to identify selective GPR55 agonists and antagonists. Since then, several GPR55 modulator scaffolds have been reported.

The relevance of GPR55 has been explored in diverse physiological and pathological processes revealing its role in inflammation, neuropathic pain, bone physiology, diabetes and cancer.

Considering GPR55 as a new promising therapeutic target, there is a clear need for new selective and potent GPR55 modulators. This review will address a current structural update of GPR55 ligands.”

http://www.ncbi.nlm.nih.gov/pubmed/27109575

In Vitro Propagation of Cannabis sativa L. and Evaluation of Regenerated Plants for Genetic Fidelity and Cannabinoids Content for Quality Assurance.

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“Cannabis sativa L. (Marijuana; Cannabaceae), one of the oldest medicinal plants in the world, has been used throughout history for fiber, food, as well as for its psychoactive properties.

The dioecious and allogamous nature of C. sativa is the major constraint to maintain the consistency in chemical profile and overall efficacy if grown from seed. Therefore, the present optimized in vitro propagation protocol of the selected elite germplasm via direct organogenesis and quality assurance protocols using genetic and chemical profiling provide an ideal pathway for ensuring the efficacy of micropropagated Cannabis sativa germplasm.

A high frequency shoot organogenesis of C. sativa was obtained from nodal segments in 0.5 μM thidiazuron medium and 95 % in vitro rhizogenesis is obtained on half-strength MS medium supplemented with 500 mg/L activated charcoal and 2.5 μM indole-3-butyric acid. Inter Simple Sequence Repeats (ISSR) and Gas Chromatography-Flame Ionization Detection (GC-FID) are successfully used to monitor the genetic stability in micropropagated plants up to 30 passages in culture and hardened in soil for 8 months.”

http://www.ncbi.nlm.nih.gov/pubmed/27108324

Endocannabinoids signaling: Molecular mechanisms of liver regulation and diseases.

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“The endocannabinoid system (ECS) includes endocannabinoids (eCBs), cannabinoid (CB) receptors and the enzymes that are responsible for endocannabinoid production and metabolism. The ECS has been reported to be present in both brain and peripheral tissues.

Recent studies have indicated that eCBs and their receptors are involved in the development of various liver diseases. They were found to be altered in response to many danger factors.

It is generally accepted that eCB may exert a protective action via CB2 receptors in different liver diseases. However, eCBs have also been demonstrated to have pathogenic role via their CB1 receptors.

Although the therapeutic potential of CB1 receptor blockade in liver diseases is limited by its neuropsychiatric side effects, many studies have been conducted to search for novel, peripherally restricted CB1 antagonists or CB2 agonists, which may minimize their neuropsychiatric side effects in clinical use.

This review summarizes the current understanding of the ECS in liver diseases and provides evidence for the potential to develop new therapeutic strategies for the treatment of these liver diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27100518

Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrheic skin and acne treatment.

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“Acne is a common skin disease characterized by elevated sebum production and inflammation of the sebaceous glands.

We have previously shown that a non-psychotropic phytocannabinoid ((-)-cannabidiol [CBD]) exerted complex anti-acne effects by normalizing “pro-acne agents”-induced excessive sebaceous lipid production, reducing proliferation and alleviating inflammation in human SZ95 sebocytes.

Therefore, in the current study we aimed to explore the putative anti-acne effects of further non-psychotropic phytocannabinoids ((-)-cannabichromene [CBC], (-)-cannabidivarin [CBDV], (-)-cannabigerol [CBG], (-)-cannabigerovarin [CBGV] and (-)-Δ9 -tetrahydrocannabivarin [THCV]).

Viability and proliferation of human SZ95 sebocytes were investigated by MTT- and CyQUANT-assays; cell death and lipid synthesis were monitored by DilC1 (5)-SYTOX Green labelling and Nile Red staining, respectively. Inflammatory responses were investigated by monitoring expressions of selected cytokines upon lipopolysaccharide treatment (RT-qPCR, ELISA). Up to 10 μM, the phytocannabinoids only negligibly altered viability of the sebocytes, whereas high doses (≥50 μM) induced apoptosis.

Interestingly, basal sebaceous lipid synthesis was differentially modulated by the substances: CBC and THCV suppressed it, CBDV had only minor effects, whereas CBG and CBGV increased it.

Importantly, CBC, CBDV and THCV significantly reduced arachidonic acid (AA)-induced “acne-like” lipogenesis.

Moreover, THCV suppressed proliferation, and all phytocannabinoids exerted remarkable anti-inflammatory actions.

Our data suggest that CBG and CBGV may have potential in the treatment of dry-skin syndrome, whereas CBC, CBDV and especially THCV show promise to become highly efficient, novel anti-acne agents.

Moreover, based on their remarkable anti-inflammatory actions, phytocannabinoids could be efficient, yet safe novel tools in the management of cutaneous inflammations.”

http://www.ncbi.nlm.nih.gov/pubmed/27094344

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

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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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

The multiplicity of action of cannabinoids: implications for treating neurodegeneration.

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“The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the G-protein coupled CB receptors, CB(1) and CB(2).

These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands.

The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis.

Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration.

Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer’s disease, multiple sclerosis, and cerebral ischemia.

This article will discuss the experimental and clinical evidence supporting a potential role for CB-based therapies in the treatment of certain neurological diseases that feature a neurodegenerative component.”

http://www.ncbi.nlm.nih.gov/pubmed/20875047

An update on peroxisome proliferator-activated receptor (PPAR) activation by cannabinoids.

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“Some cannabinoids activate the different isoforms of peroxisome proliferator-activated receptors (PPARs; α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies.

Activation of all isoforms, but primarily PPARα and γ, mediate some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumoral, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as CB1 , CB2 and TRPV1.

PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins (FABPs).

The aim of this review is to update the evidence supporting PPAR activation by cannabinoids, and review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation.”

http://www.ncbi.nlm.nih.gov/pubmed/27077495

Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.

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“Toll-like receptors (TLRs) are the sensors of pathogen-associated molecules that trigger tailored innate immune intracellular signalling responses to initiate innate immune reactions.

Data from the experimental autoimmune encephalomyelitis (EAE) model indicates that TLR signalling machinery is a pivotal player in the development of murine EAE. To compound this, data from human studies indicate that complex interplay exists between TLR signalling and Multiple Sclerosis (MS) pathogenesis.

Cannabis-based therapies are in clinical development for the management of a variety of medical conditions, including MS. In particular Sativex®, a combination of plant-derived cannabinoids, is an oromucosal spray with efficacy in MS patients, particularly those with neuropathic pain and spasticity.

Despite this, the precise cellular and molecular mechanisms of action of Sativex® in MS patients remains unclear. This review will highlight evidence that novel interplay exists between the TLR and cannabinoid systems, both centrally and peripherally, with relevance to the pathogenesis of MS.”

http://www.ncbi.nlm.nih.gov/pubmed/27079840