Category Archives: Endocannabinoid System

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

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“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.

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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?

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“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.

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“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

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“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.

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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
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