Category Archives: Endocannabinoid System

Human serum albumin: A modulator of cannabinoid drugs.

Posted on by

International Union of Biochemistry and Molecular Biology

“The endocannabinoid system is a unique neuromodulatory system that affects a wide range of biological processes and maintains the homeostasis in all mammal body systems. In recent years, several pharmacological tools to target endocannabinoid neurotransmission have been developed, including direct and indirect cannabinoid agonists and cannabinoid antagonists. Due to their hydrophobic nature, cannabinoid agonists and antagonists need to bind specific transporters to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key determinant of drug pharmacokinetics. As HSA binds both the endocannabinoid anandamide and the active ingredient of Cannabis sativa, Δ-9-tetrahydrocannabinol, we hypothesize that HSA can be the most important carrier of cannabinoid drugs. In silico docking observations strongly indicate that HSA avidly binds the indirect cannabinoid agonists URB597, AM5206, JZL184, JZL195, and AM404, the direct cannabinoid agonists WIN55,212-2 and CP55,940, and the prototypical cannabinoid antagonist/inverse agonist SR141716. Values of the free energy for cannabinoid drugs binding to HSA range between -5.4 kcal mol-1 and -10.9 kcal mol-1 . Accounting for the HSA concentration in vivo (∼ 7.5 × 10-4 M), values of the free energy here determined suggest that the formation of the HSA:cannabinoid drug complexes may occur in vivo. Therefore, HSA appears to be an important determinant for cannabinoid efficacy and may guide the choice of the drug dose regimen to optimize drug efficacy and to avoid drug-related toxicity. ”

https://www.ncbi.nlm.nih.gov/pubmed/28976704

http://onlinelibrary.wiley.com/doi/10.1002/iub.1682/abstract

The Current Landscape of Marijuana and Pharmacogenetics.

Posted on by

Image result for cureus

“The treatment of medical conditions with cannabis and cannabinoid compounds is advancing.

Although there are numerous reports related to the genetic variations of the cannabinoid receptor, a lack of studies that examine the relationship between other pharmacogenetic markers and health outcomes currently exists.

Herein, we advocate for the legalization of marijuana in the United States in order to perform more randomized controlled trials to help elucidate the role of other pharmacogenetic targets and cannabis for use in clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/28975060

https://www.cureus.com/articles/8321-the-current-landscape-of-marijuana-and-pharmacogenetics

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.

Posted on by

Current Issue

“Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1.

The duration and severity of thermally induced seizures and the frequency of spontaneous seizures were substantially decreased. Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice.

Phenotypic rescue was associated with restoration of the excitability of inhibitory interneurons in the hippocampal dentate gyrus, an important area for seizure propagation. Reduced excitability of dentate granule neurons in response to strong depolarizing stimuli was also observed.

The beneficial effects of CBD on inhibitory neurotransmission were mimicked and occluded by an antagonist of GPR55, suggesting that therapeutic effects of CBD are mediated through this lipid-activated G protein-coupled receptor.

Our results provide critical preclinical evidence supporting treatment of epilepsy and autistic-like behaviors linked to DS with CBD. We also introduce antagonism of GPR55 as a potential therapeutic approach by illustrating its beneficial effects in DS mice.

Our study provides essential preclinical evidence needed to build a sound scientific basis for increased medicinal use of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/28973916

http://www.pnas.org/content/early/2017/09/26/1711351114

Is cannabis an effective treatment for joint pain?

Posted on by

Image result for Clin Exp Rheumatol.

“Cannabis has been used to treat pain for thousands of years.

However, since the early part of the 20th century, laws restricting cannabis use have limited its evaluation using modern scientific criteria. Over the last decade, the situation has started to change because of the increased availability of cannabis in the United States for either medical or recreational purposes, making it important to provide the public with accurate information as to the effectiveness of the drug for joint pain among other indications.

The major psychotropic component of cannabis is Δ9-tetrahydrocannabinol (THC), one of some 120 naturally occurring phytocannabinoids. Cannabidiol (CBD) is another molecule found in herbal cannabis in large amounts. Although CBD does not produce psychotropic effects, it has been shown to produce a variety of pharmacological effects. Hence, the overall effects of herbal cannabis represent the collective activity of THC, CBD and a number of minor components.

The action of THC is mediated by two major G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and CB2, and recent work has suggested that other targets may also exist. Arachidonic acid derived endocannabinoids are the normal physiological activators of the two cannabinoid receptors.

Natural phytocannabinoids and synthetic derivatives have produced clear activity in a variety of models of joint pain in animals. These effects are the result of both inhibition of pain pathway signalling (mostly CB1) and anti-inflammatory effects (mostly CB2). There are also numerous anecdotal reports of the effectiveness of smoking cannabis for joint pain.

Indeed, it is the largest medical request for the use of the drug. However, these reports generally do not extend to regulated clinical trials for rheumatic diseases. Nevertheless, the preclinical and human data that do exist indicate that the use of cannabis should be taken seriously as a potential treatment of joint pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28967368

Activation of type 2 cannabinoid receptor (CB2R) by selective agonists regulates the deposition and remodelling of the extracellular matrix.

Posted on by

Image result for Biomedicine & Pharmacotherapy

“Remodelling of the extracellular matrix and accumulation of fibronectin and collagen type I play critical roles in scar formation following glaucoma filtration surgery. The transforming growth factor β1 (TGF-β1) signal transduction pathway is involved in this process in human Tenon’s fibroblasts (HTFs).

The type 2 cannabinoid receptor (CB2R) is an important member of the cannabinoidreceptor family of G protein-coupled receptors. In this study, we investigated the effects of the CB2R agonists HU308 and JWH133 on the deposition of newly formed extracellular matrix (ECM) and the contractility of HTFs.

CB2R was expressed in HTFs. Notably, the CB2R agonists HU308 and JWH133 ameliorated TGF-β1-induced generation of fibronectin, types I and III collagen, and the expression of matrix metalloproteinase 1 (MMP-1) and MMP-3. In addition, the CB2R agonists HU308 and JWH133 ameliorated TGF-β1-induced matrix contraction and remodelling in a dose- and time-dependent manner, respectively. HU308 and JWH133 also suppressed the TGF-β1-induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK).

Based on our results, agonistic activation of CB2R exerts a protective effect on scarring during the healing of wounds from glaucoma filtration surgery.”

https://www.ncbi.nlm.nih.gov/pubmed/28958132

Cannabidiol and Palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon.

Posted on by

Clinical Science “We sought to quantify the anti-inflammatory effects of two cannabinoid drugs: cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue.  These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants.

Results:   IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants.  Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants.  CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB2antagonist AM630 and TRPV1 antagonist SB366791.  PEA effects were blocked by the PPARα antagonist GW6471.  PEA and CBD were anti-inflammatory in IBD and appendicitis explants.

Conclusion: PEA and CBD are anti-inflammatory in the human colon.  This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.”

https://www.ncbi.nlm.nih.gov/pubmed/28954820

http://www.clinsci.org/content/early/2017/09/26/CS20171288

Synergistic interaction of the cannabinoid and death receptor systems: A potential target for future cancer therapies?

Posted on by

“Cannabinoid receptors have been shown to interact with other receptors, including Tumor Necrosis Factor Receptor Superfamily (TNFRS) members, to induce cancer cell death. When cannabinoids and death-inducing ligands (including TRAIL) are administered together, they have been shown to synergize and demonstrate enhanced antitumor activity in vitro. Certain cannabinoid ligands have been shown to sensitize cancer cells and synergistically interact with members of the TNFRS, thus suggesting that the combination of cannabinoids with death receptor (DR) ligands induces additive or synergistic tumor cell death. This review summarizes recent findings on the interaction of the cannabinoid and DR systems and suggests possible clinical co-application of cannabinoids and DR ligands in the treatment of various malignancies.” https://www.ncbi.nlm.nih.gov/pubmed/28948607 http://onlinelibrary.wiley.com/doi/10.1002/1873-3468.12863/abstract?systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+7th+Oct+from+03.00+EDT+%2F+08%3A00+BST+%2F+12%3A30+IST+%2F+15.00+SGT+to+08.00+EDT+%2F+13.00+BST+%2F+17%3A30+IST+%2F+20.00+SGT+and+Sunday+8th+Oct+from+03.00+EDT+%2F+08%3A00+BST+%2F+12%3A30+IST+%2F+15.00+SGT+to+06.00+EDT+%2F+11.00+BST+%2F+15%3A30+IST+%2F+18.00+SGT+for+essential+maintenance.+Apologies+for+the+inconvenience+caused+.]]>

Cannabinoid CB1 Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors.

Posted on by

“An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type-1 (CB1) receptor agonists such as Δ9-tetrahydrocannabinol are increasingly utilized for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB1 agonist-like subjective effects, as reflected in the presence or absence of CB1-related discriminative-stimulus effects in laboratory subjects. Squirrel monkeys (n=8) that discriminated the CB1 full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB1 agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB1-related discriminative-stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were non-surmountably antagonized by low doses of rimonabant. Additionally, FAAH- or MGL-inhibition revealed CB1-like subjective effects produced by AEA, but not 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB1 receptor-mediated subjective effects.” https://www.ncbi.nlm.nih.gov/pubmed/28947487 http://jpet.aspetjournals.org/content/early/2017/09/25/jpet.117.244392]]>

Targeting the Endocannabinoid System to Treat Sepsis

Posted on by

“Sepsis is a complex immune disorder that can affect the function of almost all organ systems in the body. This disorder is characterised by a malfunctioning immune response to an infection that involves both pro-inflammatory and immunosuppressive mediators. This leads to severe damage and failure of vital organs, resulting in patient death. Sepsis, septic shock, and systemic inflammatory response syndrome are the leading causes of mortality in surgical intensive care unit patients internationally. The current lack of viable therapeutic treatment options for sepsis underscores our insufficient understanding of this complex disease. The endocannabinoid system, a key regulator of essential physiological functions including the immune system, has recently emerged as a potential therapeutic target for sepsis treatment. The endocannabinoid system acquires its name from the plant Cannabis Sativa, which has been used medically to treat a variety of ailments, as well as recreationally for centuries. Cannabis Sativa contains more than 60 active phytocannabinoids with the primary phytocannabinoid Δ9-tetrahydrocannabinol (THC), (6) activating both endogenous endocannabinoid receptors. The endocannabinoid system represents a potential therapeutic target in sepsis due to the presence of cannabinoid receptors (CB2) on immune cells. In this review we discuss how various targets within the endocannabinoid system can be manipulated to treat the immune consequences of sepsis. One of the targets outlined are the endocannabinoid receptors and modulation of their activity through pharmacological agonists and antagonists. Another therapeutic target covered in this review is the modulation of the endocannabinoid degradative enzyme’s activity. Modulation of degradative enzyme activity can change the levels of endogenous cannabinoids thereby altering immune activity. Overall, activation of the CB2 receptors causes immunosuppression and can be beneficial during the hyperactivated immune state of sepsis, while suppression of the CB2 receptors may be beneficial during a hypoimmune septic state. The endocannabinoid system modulates the immune response in experimental sepsis. Manipulating the endocannabinoid system may have potential therapeutic benefit in clinical sepsis where immune and inflammatory dysfunction can be detrimental. Multiple targets exist within the endocannabinoid system, e.g. the system can be targeted at the level of receptors by administration of synthetic compounds, similar to the endocannabinoids, which either increase or inhibit receptor activation to provide the desired therapeutic effect. Alternatively, the endogenous enzymes that degrade endocannabinoids or cannabinoid-like lipids can also be targeted in order to manipulate the levels of endocannabinoids. Proper identification of the septic stage is crucial to determine the adequate therapeutic response that will be most beneficial. Due to the biphasic nature of sepsis immunopathology, immune suppression through endocannabinoid modulation can help mitigate the hyper-immune response during the early septic state, while immune activation may be beneficial in later stages.” http://www.signavitae.com/2013/05/targeting-the-endocannabinoid-system-to-treat-sepsis/ http://www.signavitae.com/2013/05/targeting-the-endocannabinoid-system-to-treat-sepsis/]]>

Effects of Cannabinoid Agonists and Antagonists on Sleep and Breathing in Sprague-Dawley Rats.

Posted on by

Issue Cover “There are no pharmacological treatments for obstructive sleep apnea syndrome, but dronabinol showed promise in a small pilot study. In anesthetized rats, dronabinol attenuates reflex apnea via activation of cannabinoid (CB) receptors located on vagal afferents; an effect blocked by cannabinoid type 1 (CB1) and/or type 2 (CB2) receptor antagonists. Here, using a natural model of central sleep apnea, we examine the effects of dronabinol, alone and in combination with selective antagonists in conscious rats chronically instrumented to stage sleep and measure cessation of breathing.

RESULTS:

Dronabinol decreased the percent time spent in rapid eye movement (REM) sleep. CB receptor antagonists did not reverse this effect. Dronabinol also decreased apneas during sleep, and this apnea suppression was reversed by CB1 or CB1/CB2 receptor antagonism.

CONCLUSIONS:

Dronabinol’s effects on apneas were dependent on CB1 receptor activation, while dronabinol’s effects on REM sleep were CB receptor-independent.”
 https://www.ncbi.nlm.nih.gov/pubmed/28934522
https://academic.oup.com/sleep/article-abstract/40/9/zsx112/3926048/Effects-of-Cannabinoid-Agonists-and-Antagonists-on?redirectedFrom=fulltext
]]>