Endocannabinoid system - Wikipedia
Fructose affects enzymes involved in the synthesis and degradation of hypothalamic endocannabinoids
Endocannabinoid synthesis, release, ..
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
Organic, Bioorganic and Biochemistry
Our research group has interests in the areas of protein structure and function, nucleic acid chemistry, drug design and synthesis, and chemical genomics. Much of our work focuses on the biochemistry and molecular biology of oxidation of natural and synthetic chemicals. Areas of interest to us include: mechanisms of oxidation of arachidonic acid and endocannabinoids by cyclooxygenase and lipoxygenase enzymes, design, synthesis, and biochemical evaluation of lipoxygenase and selective cyclooxygenase-2 (COX-2) inhibitors; chemistry and biology of DNA damage by lipid oxidation products; and endogenous pathways of DNA damage in the genesis of human cancer.
Endocannabinoids: synthesis and degradation | …
Endocannabinoids were defined in 1995 as endogenous agonists of cannabinoid receptors, i.e. of the G protein-coupled receptors for cannabis's psychoactive principle, Δ9-tetrahydrocannabinol. Although there appear to be several endocannabinoids, only two of such endogenous mediators have been thoroughly studied so far: anandamide and 2-arachidonoylglycerol (2-AG). A general strategy seems to apply to the biosynthesis and degradation of anandamide and 2-AG, although the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways. “Endocannabinoid enzymes”, that is to say enzymes that catalyse endocannabinoid biosynthesis or degradation, have been identified and in some cases cloned, and will be described in this review together with their possible pharmacological targeting for therapeutic purposes. The cellular and subcellular localization and the modes for the regulation of the expression and activity of these enzymes play an important role in the functions played by the endocannabinoids under physiological and pathological conditions.
The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the frontal cortex, whereas DAGL-α was most active in the cerebellum. Comparison of the activity profiles with a global proteomics data set revealed pronounced differences. This could indicate that post-translational modification of the endocannabinoid hydrolases is important to regulate their activity. Next, the effect of genetic deletion of the CB1 receptor was studied. No difference in the enzymatic activity was found in the cerebellum, striatum, frontal cortex, and hippocampus of CB1 receptor knockout animals compared to wild type mice. Our results are in line with previous reports and indicate that the CB1 receptor exerts no regulatory control over the basal production and degradation of endocannabinoids and that genetic deletion of the CB1 receptor does not induce compensatory mechanisms in endocannabinoid hydrolase activity.
Ligands for these receptor proteins include the endocannabinoids ..
The cyclooxygenase enzymes, COX-1 and COX-2, catalyze the oxygenation of AA to produce an array of lipid mediators known as prostaglandins (PGs). Research in the Marnett lab has shown that the COX-2 enzyme can also oxygenate 2-AG and AEA, leading to the formation of PG glyceryl esters and PG ethanolamides, respectively. In either case, oxygenation terminates endocannabinoid signaling. The COX enzymes are the targets of the nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen, and COX-2 is the specific target of the newer coxibs, including celecoxib (Celebrex), and rofecoxib (Vioxx). Although both NSAIDs and coxibs work primarily through the blockade of PG synthesis from AA, there are indications that some of their effects are modulated by the cannabinoid receptors. Thus, inhibition of COX-2 may function in part by blocking endocannabinoid degradation and prolonging CB receptor signaling.
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.
Endocannabinoids: Control of Food Intake & Energy Balance
Acylamido analogs of endocannabinoids selectively …
The endocannabinoid system consists of cannabinoid molecules synthesized internally which target receptors ..
Antineoplastic Agents/chemical synthesis; ..
The endocannabinoid system ..
26/01/2017 · The endocannabinoid system plays an ..
Endocannabinoids were defined in 1995 as endogenous agonists of cannabinoid receptors, i.e
Endocannabinoids: Overview, History, Chemical Structure
Endocannabinoids are typically synthesized on demand in a calcium dependant manner by hydrolysis of phospholipid precursors . However, despite decades of effort, the biosynthetic pathways for endocannabinoid biosysnthesis are not firmly established . A novel pathway for the synthesis of anandamide has recently been published 29. Their catabolic metabolism by cyclooxygenase 2 (COX2) 30 yields a novel class of bioactive lipids known as prostamides . Prostamides are chemically similar to prostagandins, however they have a longer lifespan in the serum 32. Typically they mediate antiinflammatory events that help to balance the pro-inflammatory effects of many prostaglandins. Pharmaceutical companies have developed COX2 inhibitors to turn off the pro-inflammatory action of prostaglandins. However, these drugs also turn off the production of cardio-protective prostamideswhich has resulted in thousands of deaths. Hence, while endocannabinoids are often produced for local action, their metabolic products can have wide spread activities, often affect global homeostasis.
Endocannabinoids - an overview | ScienceDirect Topics
Endocannabinoids are the substances our bodies naturally make to stimulate these receptors. The two most well understood of these molecules are called anandamide and 2-arachidonoylglycerol (2-AG). They are synthesized on-demand from cell membrane arachidonic acid derivatives, have a local effect and short half-life before being degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
Endocannabinoids: Synthesis and degradation - …
Endocannabinoid biochemical circuitry is extremely complicated since endocannabinoids also bind other important receptors and channels either directly, or after enzymatic processing. For example, AEA is also an endovanilloid that acts on vanilloid (TRVP1) receptors . TRVP1 channels are non-selective cation channels that belong to the TRP family of proteins. They are found not only on nerve cells, but also on a variety of other cell types . TRVP1 receptors regulate pain and are responsive to heat, acid and pressure. The complexity of cannabinoids and their closely related circuitry is again apparent. Recent work shows that AEA inhibits 2-AG synthesis by activating TRVP1 receptors. Additionally, AEA on the one hand promotes lipogenesis by activating CB1 receptors, while on the other hand it inhibits lipogenesis through TRVP1 receptors . Also, TRPA1 channels, which are responsible for deep cooling activated pain are inhibited by TRVP1 activation through activation by cannabinoids . The complexity of endocannabinoid action is further underscored by the fact that the often have biphasic affects, meaning a particular response is elicited at a low dose, and the opposite affect may result from a high dose .
The regulation of lipid metabolism is a common denominator for much cannabinoid and related molecular activities. Peroxisome Proliferator Activated Receptors (PPARs) are regulators of lipid metabolism. PPAR alpha and delta promote lipid oxidation , whereas PPAR gamma promotes lipogenesis . Cannabinoids activate peroxisome PPAR alpha and PPAR delta thus increasing fat burning. They also activate PPAR gamma 53 receptors that increase fat deposition. Thus, endocannabinoids promote both fat deposition and fat oxidation. Which process dominates and under what conditions is not yet fully understood; yet genetics is certain to play a crucial role in this balancing act.
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