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Introduction to the Endocannabinoid System (cannabis) July 26 ..
In cell culture, normal cells replicate by means of mitosis about 50 or 60 times, and then are instructed to undergo PCD (programmed cell death). This is called the . For cancer cells, the Hayflick Limit does not apply, as cancer cells are immortal and will replicate indefinitely. Cancer cells have escaped the final instruction of programmed cell death. The cancer cell laughs at “cell senescence”, proliferates uncontrollably and is seemingly immune to normal control. This is where the endocannabinoid system and phyto-cannabinoids come in to the picture. Medicinal Cannabis restores the cancer cell’s ability to undergo programmed cell death, which is then automatically triggered, while leaving normal cells unharmed.
Classically, endogenous fatty acid ethanolamides and their derivatives that bind to the cannabinoid receptors and trigger a signalling pathway are referred to as endocannabinoids. Although derivatives of arachidonic acid, including arachidonylethanolamine or anandamide, are the known endogenous ligands for cannabinoid receptors, other fatty acid ethanolamides or ‐acylethanolamines (NAE) that vary in carbon chain length and saturation occur ubiquitously in eukaryotic organisms and play an important role in their physiology and development. The metabolic pathway for NAEs is highly conserved among eukaryotes and well characterised in mammalian systems. Although NAE pathway is only partly elucidated in plants, significant progress has been made in the past 20 years in understanding the implications of the metabolism of saturated and unsaturated endocannabinoid‐like molecules in plant development and growth. The latest advancements in the field of plant endocannabinoid research are reviewed.
The Endocannabinoid System Is Dysregulated in ..
Ther Clin Risk Manag. 2008 Feb;4(1):245-59.
Cannabinoids in the management of difficult to treat pain.
Russo EB. GW Pharmaceuticals Vashon, WA, USA.
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
The analgesic effects of endocannabinoids are believed to occur at central pain pathways, so the investigators tested the ability of (R)-profens to block endocannabinoid oxygenation in cultures of dorsal root ganglion cells (Figure 5). These cultures, prepared from mouse embryos, contain a mixture of neurons and glial cells. Treatment of the cells with inflammatory stimuli induced COX-2 expression in the cells, leading to the production of PGs, PG-Gs, and PG-EAs. Treatment with all three (R)-profens blocked PG-G and PG-EA synthesis, but not the synthesis of PGs. Furthermore, (R)-profen treatment led to increased levels of 2-AG and AEA, but not AA in the stimulated cultures
Biosynthesis and the Human Endocannabinoid System: …
The discovery of what is going wrong, both in the central nervous system and the rest of the body, is key to understanding the disease and can lead us towards the following research ideals:1. being able to develop therapies for the treatment of MS2. aiding in the speed and accuracy of disease diagnosis3. improving the quality of life of the person with MS.
Prior studies had indicated that elevation of brain AEA levels through use of a FAAH inhibitor reduces anxiety in mice, so the Patel lab investigated the anxiolytic effects of LM-4131. In three separate mouse models of anxiety, LM-4131 was effective, with activity similar to a well-characterized FAAH inhibitor. LM-4131 had no anxiolytic activity in COX-2 knockout mice, confirming that its mechanism of action depended on inhibition of COX-2. The finding that LM-4131 was also ineffective in CB1 knockout mice or in wild-type mice treated with a CB1 antagonist confirmed that its anxiolytic activity required a functioning endocannabinoid signaling system.
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Mechanisms regulating melanogenesis* - SciELO
AM-8138 (Figure 3) is the first example of a molecule that selectively potentiates PG-G synthesis while having no effect on PG synthesis. Its discovery was the result of a screen of AA analogs as substrates and/or modulators of COX-2 activity. AM-8138 was not a substrate for the enzyme, and it had no effect at all on PG formation from AA. However, it increased PG-G production from 2-AG, by up to five-fold, with maximal effects occurring at a concentration of 10 μM. X-Ray crystallography of a complex of COX-2 with AM-8138 revealed that the molecule binds in an “upside-down” orientation with regard to the productive binding mode of AA in the active site. It is interesting to note, however, that crystal structures of complexes of COX-2 and AA reveal the productive conformation of AA in only one monomer, while in the second monomer, AA adopts an upside-down orientation similar to that of AM-8138.
Anais Brasileiros de Dermatologia Print version ISSN 0365-0596 An
The cyclooxygenase enzymes (COX-1 and COX-2) catalyze the first and second steps in the biosynthesis of a class of oxygen-containing lipid signaling molecules known as prostaglandins (PGs). The product of the COX reaction, PGH2, is further metabolized by other enzymes to yield five distinct final products (Figure 1). In addition, COX-2 can also use some ester and amide derivatives of AA, including AEA and 2-AG, as substrates. As shown in Figure 1, COX-2-mediated metabolism of 2-AG produces the glyceryl ester of PGH2 (PGH2-G), which then gives rise to four distinct glyceryl ester final products. The importance of PG biosynthesis in a range of physiological processes is highlighted by the fact that the widely used nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen, act primarily by blocking the activity of the COX enzymes. In contrast, the role of COX-2-mediated endocannabinoid oxygenation is not fully understood, but increasing evidence suggests that it contributes to the modulation of endocannabinoid tone in the central nervous system.
vol.88 no.1 Rio de Janeiro Jan./Feb
An exciting discovery in the Marnett lab provides a way to suppress endocannabinoid degradation and prolong signaling with a high degree of specificity. They found that certain NSAID derivatives, designated substrate-selective inhibitors (SSIs), potently inhibit COX-2-dependent oxygenation of AEA and 2-AG with little to no effect on AA oxygenation. Experiments using site-directed mutations of COX-2 revealed a key ion pairing/hydrogen bonding interaction required for inhibition of AA but not endocannabinoid oxygenation by some NSAIDs. This finding suggested that tertiary amides of the NSAID indomethacin should have SSI activity. Synthesis of a series of such compounds led to LM-4131, the morpholino amide of indomethacin (Figure 2). LM-4131 inhibited the oxygenation of 2-AG by COX-2 with an IC50 (concentration that causes 50% inhibition) of 622 nM, while having no effect on the oxygenation of AA. LM-4131 also had no effect on the activity of FAAH or MAGL in vitro.
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