The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Thomas J Feuerstein - One of the best experts on this subject based on the ideXlab platform.
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Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.
Neuroscience letters, 2005Co-Authors: Marc Steffens, Andreas Schulze-bonhage, Rainer Surges, Thomas J FeuersteinAbstract:Abstract Increased levels of the endocannabinoid anandamide (AEA) have been observed in connection with neuronal disorders like epilepsy. In order to investigate whEther an impaired enzymatic AEA hydrolysis contributes to this phenomenon, the present study determined the activity of fatty acid amidohydrolase (FAAH) in epileptic and non-epileptic human neocortical brain tissue. Additionally, we investigated whEther other putative endocannabinoids (2-arachidonylglycerol (2-AG), Noladin Ether, virodhamine) may also interact with FAAH. AEA hydrolysis was measured by the formation of the product [ 3 H]-ethanolamine after separation from the substrate using activated charcoal. FAAH activity was found to be similar in epileptic and non-epileptic human neocortex (0.29 and 0.37 nmol ethanolamine/mg protein/min, respectively). FAAH activity was about 55% higher in rat neocortex. While in human, neocortex Noladin Ether did not influence AEA hydrolysis, FAAH activity was concentration-dependently inhibited by AEA, 2-AG and virodhamine (IC 50 values 3.3, 3.5 and 13.8 μM, respectively). Our results suggest that, in the course of epilepsy, increased AEA levels are likely due to enhanced formation and not due to decreased hydrolysis. To further increase endocannabinoid activity, the application of FAAH inhibitors might be therapeutically useful in the treatment of neuronal hyperexcitability. Whereas Noladin Ether did not interact with AEA hydrolysis, this compound, 2-AG and virodhamine may share common enzymatic inactivation mechanisms in human neocortex.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:Abstract We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB 1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB 1/2 agonist [ 3 H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [ 3 H]-CP55.940 binding ( K i : 98, 1740 nM, respectively). Protease inhibition decreased the K i value of virodhamine ( K i : 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity ( K i > 10 μM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC 50 : 69, 427 nM, respectively) to the same extent as by CP55.940 ( I max each ∼30%). Inhibitions by AEA or Noladin Ether were blocked by the CB 1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by ∼20%. 2-AG had no effect; in presence of AM251, however, 10 μM 2-AG stimulated cAMP formation by ∼15%. Our results suggest, that AEA and Noladin Ether are full CB 1 receptor agonists in human neocortex, whereas virodhamine may act as a CB 1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB 1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB1/2 agonist [3H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [3H]-CP55.940 binding (Ki: 98, 1740 nM, respectively). Protease inhibition decreased the Ki value of virodhamine (Ki: 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity (Ki lymphoblasic )10 microM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC50: 69, 427 nM, respectively) to the same extent as by CP55.940 (Imax each approximately 30%). Inhibitions by AEA or Noladin Ether were blocked by the CB1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by approximately 20%. 2-AG had no effect; in presence of AM251, however, 10 microM 2-AG stimulated cAMP formation by approximately 15%. Our results suggest, that AEA and Noladin Ether are full CB1 receptor agonists in human neocortex, whereas virodhamine may act as a CB1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.
Marc Steffens - One of the best experts on this subject based on the ideXlab platform.
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Fatty acid amidohydrolase in human neocortex-activity in epileptic and non-epileptic brain tissue and inhibition by putative endocannabinoids.
Neuroscience letters, 2005Co-Authors: Marc Steffens, Andreas Schulze-bonhage, Rainer Surges, Thomas J FeuersteinAbstract:Abstract Increased levels of the endocannabinoid anandamide (AEA) have been observed in connection with neuronal disorders like epilepsy. In order to investigate whEther an impaired enzymatic AEA hydrolysis contributes to this phenomenon, the present study determined the activity of fatty acid amidohydrolase (FAAH) in epileptic and non-epileptic human neocortical brain tissue. Additionally, we investigated whEther other putative endocannabinoids (2-arachidonylglycerol (2-AG), Noladin Ether, virodhamine) may also interact with FAAH. AEA hydrolysis was measured by the formation of the product [ 3 H]-ethanolamine after separation from the substrate using activated charcoal. FAAH activity was found to be similar in epileptic and non-epileptic human neocortex (0.29 and 0.37 nmol ethanolamine/mg protein/min, respectively). FAAH activity was about 55% higher in rat neocortex. While in human, neocortex Noladin Ether did not influence AEA hydrolysis, FAAH activity was concentration-dependently inhibited by AEA, 2-AG and virodhamine (IC 50 values 3.3, 3.5 and 13.8 μM, respectively). Our results suggest that, in the course of epilepsy, increased AEA levels are likely due to enhanced formation and not due to decreased hydrolysis. To further increase endocannabinoid activity, the application of FAAH inhibitors might be therapeutically useful in the treatment of neuronal hyperexcitability. Whereas Noladin Ether did not interact with AEA hydrolysis, this compound, 2-AG and virodhamine may share common enzymatic inactivation mechanisms in human neocortex.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:Abstract We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB 1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB 1/2 agonist [ 3 H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [ 3 H]-CP55.940 binding ( K i : 98, 1740 nM, respectively). Protease inhibition decreased the K i value of virodhamine ( K i : 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity ( K i > 10 μM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC 50 : 69, 427 nM, respectively) to the same extent as by CP55.940 ( I max each ∼30%). Inhibitions by AEA or Noladin Ether were blocked by the CB 1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by ∼20%. 2-AG had no effect; in presence of AM251, however, 10 μM 2-AG stimulated cAMP formation by ∼15%. Our results suggest, that AEA and Noladin Ether are full CB 1 receptor agonists in human neocortex, whereas virodhamine may act as a CB 1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB 1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB1/2 agonist [3H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [3H]-CP55.940 binding (Ki: 98, 1740 nM, respectively). Protease inhibition decreased the Ki value of virodhamine (Ki: 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity (Ki lymphoblasic )10 microM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC50: 69, 427 nM, respectively) to the same extent as by CP55.940 (Imax each approximately 30%). Inhibitions by AEA or Noladin Ether were blocked by the CB1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by approximately 20%. 2-AG had no effect; in presence of AM251, however, 10 microM 2-AG stimulated cAMP formation by approximately 15%. Our results suggest, that AEA and Noladin Ether are full CB1 receptor agonists in human neocortex, whereas virodhamine may act as a CB1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.
Basalingappa L. Hungund - One of the best experts on this subject based on the ideXlab platform.
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role of the endocannabinoid system in the development of tolerance to alcohol
Alcohol and Alcoholism, 2005Co-Authors: Balapal S. Basavarajappa, Basalingappa L. HungundAbstract:The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB(1) receptor), which was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol Ether (Noladin Ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of Delta(9)-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB(1) receptors and its signal transduction. The observed downregulation of CB(1) receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB(1) receptor function in the brain, consistent with other studies in which the CB(1) receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB(1) receptor system promoted alcohol craving, suggesting a role for the CB(1) receptor gene in excessive alcohol drinking behaviour and development of alcoholism. Ongoing investigations may lead to a better understanding of the mechanisms underlying the development of tolerance to alcohol and to develop therapeutic strategies to treat alcoholism.
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SPECIAL ISSUE ARTICLE ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL
2004Co-Authors: Balapal S. Basavarajappa, Basalingappa L. HungundAbstract:Abstract — The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB 1 receptor), which was activated by ∆ 9-tetrahydrocannabinol ( ∆ 9-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol Ether (Noladin Ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of ∆ 9-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB 1 receptors and its signal transduction. The observed downregulation of CB 1 receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB 1 receptor function in the brain, consistent with other studies in which the CB 1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB 1 receptor system promoted alcohol craving, suggesting a role for the C
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SPECIAL ISSUE ARTICLE ROLE OF THE ENDOCANNABINOID SYSTEM IN THE DEVELOPMENT OF TOLERANCE TO ALCOHOL
2004Co-Authors: Balapal S. Basavarajappa, Basalingappa L. HungundAbstract:Abstract — The present review evaluates the evidence that the endocannabinoid system plays in the development of tolerance to alcohol. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor), which was activated by ∆9-tetrahydrocannabinol (∆9-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. Until now, four fatty acid derivatives identified to be arachidonylethanolamide (AEA), 2-arachidonylglycerol (2-AG), 2-arachidonylglycerol Ether (Noladin Ether) and virodhamine have been isolated from both nervous and peripheral tissues. Both AEA and 2-AG have been shown to mimic the pharmacological and behavioural effects of ∆9-THC. The role of the endocannabinoid system in the development of tolerance to alcohol was not known until recently. Recent studies from our laboratory have implicated for the first time a role for the endocannabinoid system in development of tolerance to alcohol. Chronic alcohol treatment has been shown to down-regulate CB1 receptors and its signal transduction. The observed downregulation of CB1 receptor function results from the persistent stimulation of the receptors by AEA and 2-AG, the synthesis of which has been shown to be increased by chronic alcohol treatment. The enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid alcohol intake, have significantly reduced CB1 receptor function in the brain, consistent with other studies in which the CB1 receptor antagonist SR 141716A has been shown to block voluntary alcohol intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive alcoho
Raphael Mechoulam - One of the best experts on this subject based on the ideXlab platform.
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Comparison of the Enzymatic Stability and Intraocular Pressure Effects of 2-Arachidonylglycerol and Noladin Ether, a Novel Putative Endocannabinoid
2013Co-Authors: Krista Laine, Raphael Mechoulam, Aviva Breuer, Kristiina Järvinen, Tomi JärvinenAbstract:(AEA) and 2-arachidonylglycerol (2-AG) are known to decrease intraocular pressure (IOP). Recently, a novel putative endogenous cannabinoid, Noladin Ether, was isolated in porcine and rat brains. In the present study, both the degradation of endogenous cannabinoids in ocular tissues and the effect on IOP of 2-AG and Noladin Ether were compared. METHODS. The rates of enzymatic degradation for AEA, 2-AG, and Noladin Ether were determined in bovine cornea and iris-ciliary body homogenates. 2-AG and Noladin Ether were dissolved in either hydroxypropyl-�-cyclodextrin (HP-�-CD) or propylene glycol and administered unilaterally to the rabbit eye. IOPs were measured in the treated and untreated eyes. The CB1 receptor antagonist AM251 was administered topically 15 minutes before the cannabinoids to investigate whEther CB1 receptors mediate the effect on IOP produced b
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2 arachidonyl glyceryl Ether an endogenous agonist of the cannabinoid cb1 receptor
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Lumir Hanus, Zvi Vogel, Saleh Abulafi, Ester Fride, Aviva Breuer, Deborah E Shalev, Irina Kustanovich, Raphael MechoulamAbstract:Abstract Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids—arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series—and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, Ether-type endocannabinoid, 2-arachidonyl glyceryl Ether (Noladin Ether), isolated from porcine brain. The structure of Noladin Ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB1 cannabinoid receptor (Ki = 21.2 ± 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor (Ki > 3 μM).
Josef Zentner - One of the best experts on this subject based on the ideXlab platform.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:Abstract We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB 1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB 1/2 agonist [ 3 H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [ 3 H]-CP55.940 binding ( K i : 98, 1740 nM, respectively). Protease inhibition decreased the K i value of virodhamine ( K i : 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity ( K i > 10 μM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC 50 : 69, 427 nM, respectively) to the same extent as by CP55.940 ( I max each ∼30%). Inhibitions by AEA or Noladin Ether were blocked by the CB 1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by ∼20%. 2-AG had no effect; in presence of AM251, however, 10 μM 2-AG stimulated cAMP formation by ∼15%. Our results suggest, that AEA and Noladin Ether are full CB 1 receptor agonists in human neocortex, whereas virodhamine may act as a CB 1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB 1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.
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binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical cb1 receptor
Biochemical Pharmacology, 2005Co-Authors: Marc Steffens, Josef Zentner, Jurgen Honegger, Thomas J FeuersteinAbstract:We investigated the affinity of putative endocannabinoids (2-arachidonylglycerol, 2-AG; Noladin Ether, virodhamine) for the human neocortical CB1 receptor. Functional activity of these compounds (including anandamide, AEA) was determined by examining basal and forskolin-stimulated cAMP formation. Assays were performed with synaptosomes, prepared from fresh human neocortical tissue. Receptor affinity was assessed from competition binding experiments with the CB1/2 agonist [3H]-CP55.940 in absence or presence of a protease inhibitor to assess enzymatic stability. Noladin Ether and virodhamine inhibited [3H]-CP55.940 binding (Ki: 98, 1740 nM, respectively). Protease inhibition decreased the Ki value of virodhamine (Ki: 912 nM), but left that of Noladin Ether unchanged. 2-AG almost lacked affinity (Ki lymphoblasic )10 microM). Basal cAMP formation was unaffected by AEA and Noladin Ether, but strongly enhanced by 2-AG and virodhamine. Forskolin-stimulated cAMP formation was inhibited by AEA and Noladin Ether (IC50: 69, 427 nM, respectively) to the same extent as by CP55.940 (Imax each approximately 30%). Inhibitions by AEA or Noladin Ether were blocked by the CB1 receptor antagonist AM251. Virodhamine increased forskolin-stimulated cAMP formation, also in presence of AM251, by approximately 20%. 2-AG had no effect; in presence of AM251, however, 10 microM 2-AG stimulated cAMP formation by approximately 15%. Our results suggest, that AEA and Noladin Ether are full CB1 receptor agonists in human neocortex, whereas virodhamine may act as a CB1 receptor antagonist/inverse agonist. Particularly the (patho)physiological role of 2-AG should be further investigated, since its CB1 receptor affinity and agonist activity especially in humans might be lower than generally assumed.