Category Archives: Uncategorized

Cannabinoid Receptor 2 Activation Restricts Fibrosis and Alleviates Hydrocephalus after Intraventricular Hemorrhage.

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“Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH).

The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases.

However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model.

In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1.”

https://www.ncbi.nlm.nih.gov/pubmed/27769788

Crystal Structure of the Human Cannabinoid Receptor CB1.

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“Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use.

CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders.

Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study.

The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding.

In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.

This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.”

https://www.ncbi.nlm.nih.gov/pubmed/27768894

Therapeutic potential of fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylethanolamine acid amidase inhibitors.

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“Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anti-cancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2), or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation.

FAEs and ECs are synthesized by a series of endogenous enzymes, including N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), or phospholipase C (PLC), and their metabolism is mediated by several metabolic enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA), or cyclooxygenase-2 (COX-2).

Over the last decades, increasing the concentration of FAEs and ECs through the inhibition of degrading enzymes has been considered to be a viable therapeutic approach to enhance their anti-nociceptive and anti-inflammatory effects, as well as protecting the nervous system.”

 https://www.ncbi.nlm.nih.gov/pubmed/27766867

Structure of primary cannabinoid receptor is revealed

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“Findings give insight into designing safe and effective cannabinoid medications.”

Illustration of the CB1 receptor.

“New research is providing a more detailed view into the structure of the human cannabinoid (CB1) receptor. These findings provide key insights into how natural and synthetic cannabinoids including tetrahydrocannabinol (THC)—a primary chemical in marijuana—bind at the CB1 receptor to produce their effects. The research was funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.”

https://www.nih.gov/news-events/news-releases/structure-primary-cannabinoid-receptor-revealed

“‘Marijuana receptor’ uncovered in new study”  http://www.medicalnewstoday.com/articles/313564.php

Cannabis as Secondary Drug Is Not Associated With a Greater Risk of Death in Patients With Opiate, Cocaine, or Alcohol Dependence.

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“To assess the impact of cannabis use as secondary drug on mortality of patients with other major substance use disorders.

Positive urinary cannabis did not confer an increased risk of death in patients with severe opiate, cocaine or alcohol dependence.”

https://www.ncbi.nlm.nih.gov/pubmed/27753720

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis.

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“The endocannabinoid system comprises receptors (CB1 and CB2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT).

Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep.

For instance, SR141716A (the CB1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep.

Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20mg/Kg; ip; separately each one) to rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period.

Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine, norepinephrine, epinephrine, serotonin, as well as adenosine while VDM-11 caused a decline in contents of these molecules.

These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking.

It can be concluded that elements of the endocannabinoid system, such as the CB1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking.”

https://www.ncbi.nlm.nih.gov/pubmed/27746343

Cannabis: A Treasure Trove or Pandora’s Box?

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“Cannabis is one of the earliest cultivated plants.

Cannabis of industrial utility and culinary value is generally termed as hemp.

Conversely, cannabis that is bred for medical, spiritual and recreational purposes is called marijuana.

The female marijuana plant produces a significant quantity of bio- and psychoactive phytocannabinoids, which regained the spotlight with the discovery of the endocannabinoid system of the animals in the early 90’s.

Nevertheless, marijuana is surrounded by controversies, debates and misconceptions related to its taxonomic classification, forensic identification, medical potential, legalization and its long-term health consequences.

In the first part, we provide an in-depth review of the botany and taxonomy of Cannabis. We then overview the biosynthesis of phytocannabinoids within the glandular trichomes with emphasis on the role of peculiar plastids in the production of the secreted material. We also compile the analytical methods used to determine the phytocannabinoid composition of glandular trichomes.

In the second part, we revisit the psychobiology and molecular medicine of marijuana. We summarize our current knowledge on the recreational use of cannabis with respect to the modes of consumption, short-term effects, chronic health consequences and cannabis use disorder.

Next, we overview the molecular targets of a dozen major and minor bioactive cannabinoids in the body. This helps us introduce the endocannabinoid system in an unprecedented detail: its up-to-date molecular biology, pharmacology, physiology and medical significance, and beyond.

In conclusion, we offer an unbiased survey about cannabis to help better weigh its medical value versus the associated risks.”

https://www.ncbi.nlm.nih.gov/pubmed/27719666

From Fertilisation to Implantation in Mammalian Pregnancy-Modulation of Early Human Reproduction by the Endocannabinoid System.

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“There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol) in early reproduction.”

https://www.ncbi.nlm.nih.gov/pubmed/27713383

The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism.

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“Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects.

Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC).

The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system.

Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling.

We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.”

 https://www.ncbi.nlm.nih.gov/pubmed/27713369

Activation of Cannabinoid Receptor 2 Attenuates Mechanical Allodynia and Neuroinflammatory Responses in a Chronic Post-Ischemic Pain Model of Complex Regional Pain Syndrome Type I in Rats.

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“Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized.

Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes.

In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord.

Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation.

We hypothesized that CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling.

We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking).

Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord.

MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630.

Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.”

https://www.ncbi.nlm.nih.gov/pubmed/27717112