Assay of Endocannabinoid Uptake

Rau, Mark; Nicolussi, Simon; Chicca, Andrea; Gertsch, Jürg

doi:10.1007/978-1-4939-3539-0_20

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…Next, we assessed whether pharmacologically inhibitable AEA uptake by the putative EMT (Chicca et al, 2012;Nicolussi and Gertsch, 2015) was observable in these cells. By monitoring the uptake of radiolabeled [ 3 H]AEA by the cells, we found that acute inhibition (15 minutes, 10 mmol/L) of AEA cellular uptake using the reference eCB transport inhibitor UCM707 (Ló pez-Rodríguez et al, 2003;Rau et al, 2016) was able to significantly alter the eCB uptake process. UCM707 reduced the intracellular [ 3 H]AEA signal, which was accompanied by a significant increase in extracellular [ 3 H]AEA levels compared with vehicle control.…”

Section: Sebocytes Exhibit a Pharmacologically Inhibitable Ecb Uptakementioning

confidence: 96%

Endocannabinoid Tone Regulates Human Sebocyte Biology

Zákány

Oláh

Markovics

et al. 2018

Journal of Investigative Dermatology

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We have previously shown that endocannabinoids (eCBs) (e.g., anandamide) are involved in the maintenance of homeostatic sebaceous lipid production in human sebaceous glands and that eCB treatment dramatically increases sebaceous lipid production. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes and to study the effects of eCB uptake inhibitors on human SZ95 sebocytes, thus exploring the role of the putative eCB membrane transporter, which has been hypothesized to facilitate the cellular uptake and subsequent degradation of eCBs. We found that the major eCB synthesizing (N-acyl phosphatidylethanolamine-specific phospholipase D, and diacylglycerol lipase-α and -β) and degrading (fatty acid amide hydrolase, monoacylglycerol lipase) enzymes are expressed in SZ95 sebocytes and also in sebaceous glands (except for diacylglycerol lipase-α, the staining of which was dubious in histological preparations). eCB uptake-inhibition with VDM11 induced a moderate increase in sebaceous lipid production and also elevated the levels of various eCBs and related acylethanolamides. Finally, we found that VDM11 was able to interfere with the proinflammatory action of the TLR4 activator lipopolysaccharide. Collectively, our data suggest that inhibition of eCB uptake exerts anti-inflammatory actions and elevates both sebaceous lipid production and eCB levels; thus, these inhibitors might be beneficial in cutaneous inflammatory conditions accompanied by dry skin.

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Section: Sebocytes Exhibit a Pharmacologically Inhibitable Ecb Uptakementioning

confidence: 96%

Endocannabinoid Tone Regulates Human Sebocyte Biology

Zákány

Oláh

Markovics

et al. 2018

Journal of Investigative Dermatology

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“…Among these, facilitated diffusion is influenced by both the interaction of eCBs with extra-and intracellular binding proteins and their metabolic enzymes. The measurement of facilitated diffusion and plasma membrane lipid transport is challenging and demands special phenotypic assays not easily accessible for routine screening Fowler, 2013;Rau et al, 2016;Reynoso-Moreno et al, 2023). A major challenge has been to differentiate FAAH and AEA uptake inhibitors as these processes are intrinsically coupled (Fowler et al, 2004;Vandevoorde and Fowler, 2005;Hillard et al, 2007).…”

Section: Therapeutic Potential Of Monoacylglycerol Lipase (Magl)mentioning

confidence: 99%

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

et al. 2023

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The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide. Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ 9tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) -made of receptors, metabolic enzymes and transporters -that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. Significance Statement -The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB 1 R and CB 2 R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.

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Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

et al. 2019

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Guineensine ((2E,4E,12E)‐13‐(benzo[d][1,3]dioxol‐5‐yl)‐N‐isobutyltrideca‐2,4,12‐trienamide) is a plant‐derived natural product that inhibits reuptake of the endocannabinoid anandamide with sub‐micromolar potency. We have established a highly efficient total synthesis of guineensine, which provided the natural product in only five steps from commercially available 3‐nonyn‐1‐ol in 17 % overall yield, relying on the attachment of the benzodioxolyl moiety to the unsaturated fatty acid chain by means of a Suzuki coupling as the key step. Subsequent SAR studies revealed that replacement of the N‐isobutyl group in the natural product by various alkyl, arylalkyl, or aryl groups is generally well tolerated, and derivatives could be identified that are slightly more potent anandamide reuptake inhibitors than guineensine itself. In contrast, modifications of the benzodioxolyl moiety led to decreased activity. Intriguingly, a change in the configuration of the C4=C5 double bond from E to Z was found to be very well tolerated, in spite of the associated change in the overall geometry of the molecule.

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Assay of Endocannabinoid Uptake

Cited by 4 publications

References 21 publications

Endocannabinoid Tone Regulates Human Sebocyte Biology

Endocannabinoid Tone Regulates Human Sebocyte Biology

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

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