Quantitation of polyamines in hypothalamus and pituitary of female and male developing rats

Thyssen, Sandra M.; Libertun, Carlos

doi:10.1016/s0304-3940(02)00097-6

Cited by 7 publications

(3 citation statements)

References 18 publications

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“…The agmatine system is widely but unevenly distributed among tissues and tissue cell types (778). Agmatine is present at a high level in the hypothalamus (779) and has recently been detected in the anterior pituitary as well (780). Since FS cells already have the machinery to use arginine for NO signalling, it would be worthwhile to investigate whether FS cells are also the site for agmatine formation in the anterior pituitary and whether agmatine has effects on hormone secretion or cellular differentiation, either directly or via its effects on the NO system.…”

Section: Paracrine Control By Nonhormonal Cellsmentioning

confidence: 99%

Endogenous Cannabinoids: Structure and Metabolism

Bisogno

2008

J Neuroendocrinology

144

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D9 -Tetrahydrocannabinol (THC), the main psychoactive compound extracted from Cannabis sativa, is the most representative component of the mixture of therapeutic substances that are communally referred to as cannabinoids (1). It acts as an agonist at specific G-protein-coupled receptors, cannabinoid receptor subtypes CB 1 and CB 2 (2). The discovery of cannabinoid receptors has driven the investigation of the existence of their natural ligands and, soon after, endocannabinoids were identified. N-arachidonoyl-ethanolamine (AEA, anandamide) and 2-arachidonoyl glycerol (2-AG) are the two most studied endocannabinoids. They are biosynthesised 'on demand' by cleavage of their membrane lipid precursors N-arachidonoyl-phosphatidylethanolamine (N-ArPE) and sn-1-acyl-2-arachidonoylglycerols (DAGs) respectively, and then inactivated by intracellular hydrolysing enzymes. Cannabinoid receptors, endocannabinoids and enzymes that biosynthesise [N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL)] and degrade [fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipases (MAGL)] AEA and 2-AG, respectively, are key components in the endocannabinoid system (3). Despite a large number of excellent studies having contributed to the current understanding of the endocannabinoid regulation and function, further efforts are necessary to fully comprehend this signalling system. Here, a review on the current knowledge on structure and metabolism of the best studied endogenous cannabinoids is presented. In particular, this review concentrates on the mechanisms responsible for the biosynthesis and inactivation of the endocannabinoids, as well as on the several inhibitors of their metabolism identified to date. Endocannabinoids and related N-acyl-ethanolaminesEndocannabinoids are defined as endogenous compounds capable of binding to and functionally activating cannabinoid receptors. At least five endocannabinoids have been identified to date (Fig. 1). Anandamide, the amide between arachidonic acid and ethanolamine, was the first endogenous ligand to be reported at the end of 1992 (4) and additional polyunsaturated ethanolamines that bind to cannabinoid receptors, homolinolenylethanolamide and docosatetraenylethanolamide, have been isolated in the brain. Other endocannabinoids, all derived from arachidonic acid, were identified. The identification of 2-AG, the ester of arachidonic acid with glycerol, isolated from canine gut and brain has also been reported (5, 6). Subsequently, the first endocannabinoid characterised by ether bond, 2-arachidonyl glyceryl ether or noladin ether, was isolated from porcine brain (7) and N-arachidonoyldopamine (NADA), a selective CB 1 agonist and a potent agonist of vanilloid receptors, was discovered (8, 9). O-arachidonoylethanolamine, the ester derivative of ethanolamine with arachidonic acid, with the same molecular weight as anandamide but with opposite orientation of the polar ethanolamine moiety, was named virodhamine from the Sanskrit word virodha, ...

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Section: Paracrine Control By Nonhormonal Cellsmentioning

confidence: 99%

Endogenous Cannabinoids: Structure and Metabolism

Bisogno

2008

J Neuroendocrinology

144

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“…The lack of prior high throughput screening efforts directed at ODC is due in part to the difficulty in assaying its activity. Classical assay methods utilize capture of 14 CO 2 from radiolabeled ornithine or derivatization of putrescine followed by high pressure liquid chromatography analysis (29,30). Neither of these techniques is tenable for a large scale screening effort.…”

mentioning

confidence: 99%

Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase

Smithson

Lee

Shelat

et al. 2010

Journal of Biological Chemistry

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Human African trypanosomiasis, caused by the eukaryotic parasite Trypanosoma brucei, is a serious health problem in much of central Africa. The only validated molecular target for treatment of human African trypanosomiasis is ornithine decarboxylase (ODC), which catalyzes the first step in polyamine metabolism. Here, we describe the use of an enzymatic high throughput screen of 316,114 unique molecules to identify potent and selective inhibitors of ODC. This screen identified four novel families of ODC inhibitors, including the first inhibitors selective for the parasitic enzyme. These compounds display unique binding modes, suggesting the presence of allosteric regulatory sites on the enzyme. Docking of a subset of these inhibitors, coupled with mutagenesis, also supports the existence of these allosteric sites.

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“…Classical methods for assaying decarboxylase function often involve capture of 14 CO 2 from radiolabeled substrates or derivatization of the enzyme products followed by HPLC analysis. 6,7 Neither of these techniques is suitable for high-throughput screening (HTS) efforts, as they involve either formation of radioactive gas or lengthy, resource intensive detection procedures. Use of a commercial low-throughput method linking the production of CO 2 to the consumption of NADH using phosphoenolpyruvate carboxylase (PEPC) and malate dehydrogenase (MDH) to track decarboxylase activities has been reported 8 ( Scheme 1 ).…”

mentioning

confidence: 99%

Optimization of a Non-Radioactive High-Throughput Assay for Decarboxylase Enzymes

Smithson

Shelat

Baldwin

et al. 2010

ASSAY and Drug Development Technologies

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Herein, we describe the optimization of a linked enzyme assay suitable for high-throughput screening of decarboxylases, a target family whose activity has historically been difficult to quantify. Our approach uses a commercially available bicarbonate detection reagent to measure decarboxylase activity. The assay is performed in a fully enclosed automated screening system under inert nitrogen atmosphere to minimize perturbation by exogenous CO2. Receiver operating characteristic (ROC) analysis following a pilot screen of a small library of approximately 3,600 unique molecules for inhibitors of Trypanosoma brucei ornithine decarboxylase quantitatively demonstrates that the assay has excellent discriminatory power (area under the curve = 0.90 with 95% confidence interval between 0.82 and 0.97).

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Quantitation of polyamines in hypothalamus and pituitary of female and male developing rats

Cited by 7 publications

References 18 publications

Endogenous Cannabinoids: Structure and Metabolism

Endogenous Cannabinoids: Structure and Metabolism

Discovery of Potent and Selective Inhibitors of Trypanosoma brucei Ornithine Decarboxylase

Optimization of a Non-Radioactive High-Throughput Assay for Decarboxylase Enzymes

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