Tag Archives: therapeutic

The endocannabinoid system: no longer anonymous in the control of nitrergic signalling?

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“The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the regulation of diverse cellular functions. Importantly, growing evidence suggests that the biological actions of the ECS may, in part, be mediated through its ability to regulate the production and/or release of nitric oxide, a ubiquitous bioactive molecule, which functions as a versatile signalling intermediate. Herein, we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production, as well as the involvement of reactive nitrogen species in regulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function. Importantly, the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature, depending on cellular context. Moreover, such crosstalk may act to maintain proper cell function, whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysregulation. Consequently, future studies targeting these signalling systems may provide new insights into the potential role of the ECS -: nitric oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological, cardiovascular, and metabolic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/28130308

A cannabigerol-rich Cannabis sativa extract, devoid of [INCREMENT]9-tetrahydrocannabinol, elicits hyperphagia in rats.

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“Nonpsychoactive phytocannabinoids (pCBs) from Cannabis sativa may represent novel therapeutic options for cachexia because of their pleiotropic pharmacological activities, including appetite stimulation.

We have recently shown that purified cannabigerol (CBG) is a novel appetite stimulant in rats.

As standardized extracts from Cannabis chemotypes dominant in one pCB [botanical drug substances (BDSs)] often show greater efficacy and/or potency than purified pCBs, we investigated the effects of a CBG-rich BDS, devoid of psychoactive [INCREMENT]-tetrahydrocannabinol, on feeding behaviour.

CBG-BDS is a novel appetite stimulant, which may have greater potency than purified CBG, despite the absence of [INCREMENT]-tetrahydrocannabinol in the extract.”

https://www.ncbi.nlm.nih.gov/pubmed/28125508

Molecular Pharmacology of Phytocannabinoids.

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“Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years.

The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content.

Δ9-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2.

Δ9-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ9-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis.

This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene.

The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond.

The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects.

The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.”

https://www.ncbi.nlm.nih.gov/pubmed/28120231

Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain.

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“Sulfur dioxide (SO2) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. However, there are currently no effective medications targeting the harmful outcomes from chemical inhalation.

Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.

Here, we indicated that endogenous 2-AG protected against neuroinflammation in response to SO2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS).

In addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO2 inhalation by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2).

In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.

Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO2 inhalation.”

https://www.ncbi.nlm.nih.gov/pubmed/28115138

β-Caryophyllene promotes osteoblastic mineralization, and suppresses osteoclastogenesis and adipogenesis in mouse bone marrow cultures in vitro.

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“Osteoporosis is induced by the reduction in bone mass through decreased osteoblastic osteogenesis and increased osteoclastic bone resorption, and it is associated with obesity and diabetes. Osteoblasts and adipocytes are derived from bone marrow mesenchymal stem cells. The prevention of osteoporosis is an important public health concern in aging populations. β-caryophyllene, a component of various essential oils, is a selective agonist of the cannabinoid receptor type 2 and exerts cannabimimetic anti-inflammatory effects in animals. The present study aimed to identify the effect of β-caryophyllene on adipogenesis, osteoblastic mineralization and osteoclastogenesis in mouse bone marrow cell cultures in vitro. Bone marrow cells obtained from mouse femoral tissues were cultured in the presence of β-caryophyllene (0.1-100 µM) in vitro. The results revealed that β-caryophyllene stimulated osteoblastic mineralization, and suppressed adipogenesis and osteoclastogenesis. Thus, β-caryophyllene may be used as a therapeutic agent for the prevention and treatment of osteoporosis.”

https://www.ncbi.nlm.nih.gov/pubmed/28105093

“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

The Endocannabinoid System and Its Role in Eczematous Dermatoses.

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“The skin serves as the foremost barrier between the internal body and the external world, providing crucial protection against pathogens and chemical, mechanical, and ultraviolet damages. The skin is a central player in the intricate network of immune, neurologic, and endocrine systems. The endocannabinoid system (ECS) includes an extensive network of bioactive lipid mediators and their receptors, functions to modulate appetite, pain, mood, and memory, and has recently been implicated in skin homeostasis. Disruption of ECS homeostasis is implicated in the pathogenesis of several prevalent skin conditions. In this review, we highlight the role of endocannabinoids in maintaining skin health and homeostasis and discuss evidence on the role of ECS in several eczematous dermatoses including atopic dermatitis, asteatotic eczema, irritant contact dermatitis, allergic contact dermatitis, and chronic pruritus. The compilation of evidence may spark directions for future investigations on how the ECS may be a therapeutic target for dermatologic conditions.” https://www.ncbi.nlm.nih.gov/pubmed/28098721

“The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

Cannabinoids – a new weapon against cancer?

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“Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent.

The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern medicine.

Many scientific studies indicate the potential use of cannabinoids in the fight against cancer.

Experiments carried out on cell lines in vitro and on animal models in vivo have shown that phytocannabinoids, endocannabinoids, synthetic cannabinoids and their analogues can lead to inhibition of the growth of many tumor types, exerting cytostatic and cytotoxic neoplastic effect on cells thereby negatively influencing neo-angiogenesis and the ability of cells to metastasize.

The main molecular mechanism leading to inhibition of proliferation of cancer cells by cannabinoids is apoptosis. Studies have shown, however, that the process of apoptosis in cells, treated with recannabinoids, is a consequence of induction of endoplasmic reticulum stress and autophagy. On the other hand, in the cellular context and dosage dependence, cannabinoids may enhance the proliferation of tumor cells by suppressing the immune system or by activating mitogenic factors.

Leading from this there is a an obvious need to further explore cannabinoid associated molecular pathways making it possible to develop safe therapeutic drug agents for patients in the future.”

 https://www.ncbi.nlm.nih.gov/pubmed/28100841

Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.

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“The identification and cloning of the two major cannabinoid (CB1 and CB2) receptors together with the discovery of their endogenous ligands in the late 80s and early 90s, resulted in a major effort aimed at understanding the mechanisms and physiological roles of the endocannabinoid system (ECS). Due to its expression and localization in the central nervous system (CNS), the CB1 receptor together with its endogenous ligands (endocannabinoids (eCB)) and the enzymes involved in their synthesis and degradation, has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others. In this review, we will provide a general overview of the ECS with emphasis on the CB1 receptor in health and disease. We will describe our current understanding of the complex aspects of receptor signaling and trafficking, including the non-canonical signaling pathways such as those mediated by β-arrestins within the context of functional selectivity and ligand bias. Finally, we will highlight some of the disorders in which CB1 receptors have been implicated. Significant knowledge has been achieved over the last 30 years. However, much more research is still needed to fully understand the complex roles of the ECS, particularly in vivo and to unlock its true potential as a source of therapeutic targets.”

https://www.ncbi.nlm.nih.gov/pubmed/28101004

Compensatory Activation of Cannabinoid CB2 Receptor Inhibition of GABA Release in the Rostral Ventromedial Medulla in Inflammatory Pain.

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“The rostral ventromedial medulla (RVM) is a relay in the descending pain modulatory system and an important site of endocannabinoid modulation of pain.

Our data provide evidence that CB2 receptor function emerges in the RVM in persistent inflammation and that selective CB2 receptor agonists may be useful for treatment of persistent inflammatory pain.

SIGNIFICANCE STATEMENT:

These studies demonstrate that endocannabinoid signaling to CB1 and CB2 receptors in adult rostral ventromedial medulla is altered in persistent inflammation. The emergence of CB2 receptor function in the rostral ventromedial medulla provides additional rationale for the development of CB2 receptor-selective agonists as useful therapeutics for chronic inflammatory pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28100744

Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers.

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“Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant.

In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA).

Despite its status, there are no well-controlled data available regarding its abuse liability.

Overall, CBD did not display any signals of abuse liability at the doses tested and these data may help inform U.S. regulatory decisions regarding CBD schedule on the CSA.”

https://www.ncbi.nlm.nih.gov/pubmed/28088032