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Jyrki Taskinen - One of the best experts on this subject based on the ideXlab platform.
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Characterization of catechol glucuronidation in rat liver.
Drug Metabolism and Disposition, 2002Co-Authors: Laurence Antonio, Joël-paul Grillasca, Brian Burchell, Marie-helene Piet, Brian T. Ethell, Mohamed Ouzzine, Sylvie Fournel-gigleux, Jyrki Taskinen, Eivor Elovaara, Jacques MagdalouAbstract:Catechols are a class of substances from natural or synthetic origin that contain a 1,2-dihydroxybenzene group. We have characterized the glucuronidation by rat liver microsomes and by the rat liver recombinant UDP-glucuronosyltransferase isoforms UGT1A6 and UGT2B1 of a series of 42 structurally diverse catechols, including neurotransmitters, polyphenols, drugs, and catechol estrogens. Small catechols (4-nitrocatechol, 2,3-dihydroxybenzaldehyde, 4-methylcatechol, and tetrachlorocatechol), tyrphostine A23, and octylgallate were glucuronidated at the highest rate by rat liver microsomes and the recombinant enzymes. By contrast, polyphenols from green tea (catechin and related compounds), 3,5-dinitrocatechol, the catechol- O -methyltransferase inhibitor drugs (entacapone, Nitecapone, and tolcapone), the carboxyl catechols (gallic acid and dihydroxybenzoic acid derivatives), and the neurotransmitters and dopaminergic drugs, except dobutamine, were glucuronidated at low rate. Glucuronidation of most catechols was increased upon treatment of rats by 3-methylcholanthrene (3-MC) or Aroclor 1254. No induction was observed after administration of phenobarbital and clofibrate or treatment with catechols. Partial least-squares modeling was carried out to explain the variations of glucuronidation activity by liver microsomes of nontreated and 3-MC-treated rats. The model developed explained 82% and predicted 61% of the variations of glucuronidation activities. Among the 17 electronic and substructure parameters used that characterize the catechols, the hydrophobicity/molar volume ratio of catechols showed a strong positive correlation with the glucuronidation rate. The effect of the p K aof the catechol group was modeled to be nonlinear, the optimal p K a value for glucuronidation being between 8 and 9. Hydrogen bonding and steric effects also were important to account for to predict the glucuronidation rates.
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Direct analysis of nitrocatechol-type glucuronides in urine by capillary electrophoresis–electrospray ionisation mass spectrometry and tandem mass spectrometry
Journal of chromatography. B Biomedical sciences and applications, 2000Co-Authors: Helena Keski-hynnilä, Jyrki Taskinen, Knut Raanaa, Risto KostiainenAbstract:Direct, quantitative capillary electrophoresis-electrospray ionisation mass spectrometric (CE-ESI-MS) and tandem mass spectrometric (CE-ESI-MS-MS) methods are described for the quantitation of 3-O-glucuronides of E- and Z-entacapone isomers (EEG and EZG) and tolcapone (TG) in urine. 3-O-Glucuronide of Nitecapone was used as internal standard. Good separation of glucuronides was achieved with 20 mM ammonium acetate as separation solution at pH 6.84. Stacking was used to increase the sensitivity of the method by introducing samples in 5 mM ammonium acetate. CE-ESI-MS and CE-ESI-MS-MS methods are linear with correlation coefficients better than 0.9983 and 0.9982, and repeatable with relative standard deviations below 9 and 14%, respectively. The limit of detection (LOD) in CE-ESI-MS at signal-to-noise ratio 3 is 100 ng/ml for EEG and EZG and 250 ng/ml for TG. The CE-ESI-MS-MS method was the more sensitive; LOD was 7 ng/ml for all compounds, without any concentration of the sample.
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Enzyme-assisted synthesis and structural characterization of nitrocatechol glucuronides.
Bioconjugate chemistry, 1999Co-Authors: Leena Luukkanen, Eivor Elovaara, Pekka Ottoila, Ilkka Kilpeläinen, Heli Kangas, Jyrki TaskinenAbstract:Enzyme-assisted synthesis and characterization are described for 3-O-β-d-glucuronides 1b−4b of the aglycons E- and Z-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide (entacapone), 1a and 2a, respectively, 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione (Nitecapone) 3a and 4‘-methyl-3,4-dihydroxy-5-nitrobenzophenone (tolcapone) 4a, and 1-o- and 2-o-glucuronides 5b and 6b of the aglycon 1,2-dihydroxy-4-nitrobenzene 5a. Liver microsomes from rats pretreated with Aroclor 1254 were used as catalyst in the synthesis. Glucuronidation was regio- and stereoselective in the case of 1a−4a; only one product was observed by HPLC, HPTLC, and NMR. The glucuronidation of 1,2-dihydroxy-4-nitrobenzene 5a resulted in equal amounts of 1-O-β-d- and 2-O-β-d-glucuronides. Purification of the crude products by C18 solid-phase extraction and/or flash chromatography gave compounds 1b−6b in 38−98% yields (50−84 mg). The structures of the glucuronides were characterized on the basis of UV and IR spectra and confi...
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Analysis of catechol-type glucuronides in urine samples by liquid chromatography-electrospray ionization-tandem mass spectrometry
Journal of Chromatography A, 1998Co-Authors: Helena Keski-hynnilä, Jyrki Taskinen, Riitta Andersin, Leena Luukkanen, Risto KostiainenAbstract:A direct and fast liquid chromatographic–electrospray ionization-tandem mass spectrometric (LC–ESI-MS–MS) method is described for the determination of 3-O-glucuronides of E- and Z-entacapone, Nitecapone and tolcapone and 1-O- and 2-O-glucuronides of 4-nitrocatechol in urine. p-Nitrophenyl β-d-glucuronide was used as internal standard. Spiked urine samples were prepared by solid-phase extraction and analysed by isocratic LC–ESI-MS–MS in negative ion mode. The ESI mass spectra showed an abundant deprotonated molecule [M–H]−, which was chosen as precursor ion. Collisionally induced dissociation of [M–H]− in MS–MS resulted in the loss of neutral glucuronide moiety and in the appearance of an intense negatively charged drug molecule, which was chosen as the product ion to be monitored in the LC–MS–MS analysis. The new method showed good linearity (r2>0.997) and repeatability of the method (relative standard deviation
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Glucuronidation of Entacapone, Nitecapone, Tolcapone, and Some Other Nitrocatechols by Rat Liver Microsomes
Pharmaceutical Research, 1997Co-Authors: Pia Lautala, Eivor Elovaara, Maija Kivimaa, Hannele Salomies, Jyrki TaskinenAbstract:Purpose . Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds. Methods . The glucuronidation kinetics of seven nitrocatechols and 4-nitrophenol, the reference substrate for phenol UDP-glucuronosyltrans-ferase activity, was measured in liver microsomes from creosote-treated rats and determined by non-linear fitting of the experimental data to the Michaelis-Menten equation. A new method that combined densitometric and radioactivity measurement of the glucuronides separated by HPTLC was developed for the quantification. Results . Apparent K_m values for the nitrocatechols varied greatly depending on substitution pattern being comparable with 4-nitrophenol (0.11 mM) only in the case of 4-nitrocatechol (0.19 mM). Simple nitrocatechols showed two-fold V_max values compared with 4-nitrophenol (68.6 nmol min^−1 mg^−1), while all disubstituted catechols exhibited much lower glucuronidation rate. V_max/K_m values were about 10 times higher for monosubstituted catechols compared to disubstituted ones. The kinetic parameters for COMT inhibitors were in the following order: K_m Nitecapone >> entacapone > tolcapone; V_max Nitecapone > entacapone > tolcapone; V_max/K_m tolcapone > Nitecapone > entacapone. Conclusions . Nitrocatechols can in principle be good substrates of UGTs. However, substituents may have a remarkable effect on the enzyme kinetic parameters. The different behaviour of Nitecapone compared to the other COMT inhibitors may be due to its hydrophilic 5-substituent. The longer elimination half-life of tolcapone in vivo compared to entacapone could not be explained by glucuronidation kinetics in vitro .
Lester Packer - One of the best experts on this subject based on the ideXlab platform.
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Handbook of Synthetic Antioxidants
2019Co-Authors: Lester PackerAbstract:General concepts: approach and rationale for the design of synthetic derivatives of natural antioxidants as therapeutic agents. Synthetic derivatives of natural antioxidants: design and biological evaluation of tissue-directed alpha-tocopherol analogs physical and chemical mechanisms of the antioxidant action of tirilazad mesylate anionic tocopherol esters as antioxidants and cytoprotectants. Phenolic antioxidants: phenolic antioxidants - physiological and toxicological aspects antioxidant properties of probucol antioxidant properties of the catechol derivative Nitecapone. Twenty-one aminosteroids or lazaroids: neuroprotective efficacy and mechanisms of the lazaroids. Sulfhydryl and selenium-containing compounds: antioxidant properties of ebselen the development of diaryl chalcogenides and alpha-(phenylselenenyl) ketones with antioxidant and glutathione peroxidase-mimetic properties modulation of glutathione. Nitrones and nitroxides: nitrones radical traps as protectors of oxidative damage in the central nervous system antioxidant properties of nitroxides and nitroxide SOD mimics. SOD mimics: mimics of superoxide dismutase. Metal chelators: antioxidant properties of synthetic iron chelators.
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Role of ascorbate in protection by Nitecapone against cardiac ischemia-reperfusion injury.
Biochemical pharmacology, 1995Co-Authors: Nobuya Haramaki, Daphne B. Stewart, Sarita Aggarwal, Teruyuki Kawabata, Lester PackerAbstract:Abstract The antioxidant properties of Nitecapone, a catechol derivative and an inhibitor of catechol- O -methyltransferase, were reported recently. In the present study, the influence of Nitecapone on isolated rat heart ischemia-reperfusion injury was investigated to elucidate its cardioprotective role. Nitecapone, administered in the perfusion buffer from the beginning of the pre-ischemic phase, significantly improved recovery of cardiac mechanical function, suppressed enzyme leakage in the coronary effluent, and minimized loss of ascorbate, compared with the control group. In rats fed a diet containing 4% ascorbate, myocardial ascorbate content in ascorbate-fed rats after ischemia-reperfusion was higher than that in control rats fed a normal diet without ischemia. However, supplemented rats did not show any beneficial effects on cardiac mechanical recovery or enzyme leakage, suggesting that maintenance of tissue ascorbate level is not the cause, but the result of the protective effects; of Nitecapone against cardiac ischemia-reperfusion injury. The iron-chelating effect of Nitecapone was also lested. It was confirmed, using electron spin resonance, that 50 μM Nitecapone chelates the same concentration of iron released from the heart into the coronary effluent. Hence, the iron-chelating ability of Nitecapone may be responsible, at least in part, for its cardioprotective effects in ischemia-reperfusion injury.
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Antioxidant activity of Nitecapone and its analog OR-1246: effect of structural modification on antioxidant action.
Methods in enzymology, 1994Co-Authors: Lucia Marcocci, Yuichiro J. Suzuki, Masahiko Tsuchiya, Lester PackerAbstract:Publisher Summary This chapter discusses the antioxidant activity of Nitecapone and its analog OR-1246. The effect of structural modification on antioxidant action is also described. Nitecapone is an effective peripherally acting inhibitor of catechol O -methyl-transferase. Nitecapone scavenges superoxide, hydroxyl, and peroxyl radicals generated either in solution or in membranes, protects membranes from lipid peroxidation, recycles vitamin E through a reaction with ascorbate, and inhibits xanthine oxidase activity. The compound also form a reversible adduct with glutathione, and protect this thiol from oxidative depletion. Nitecapone exerts gastroprotective effects in various models of gastric and duodenal ulcers, and it is being evaluated in a clinical study as an antiulcer drug. Although the stimulation of duodenal bicarbonate secretion mediated by Nitecapone through the inhibition of catechol O -methyltransferase activity could explain the gastroprotective effect, the antioxidant properties of the molecule could also contribute to this protection. The chapter describes the methods used to assess the effects of the distinctive structural and physicochemical properties of Nitecapone and OR-1246 on their respective antioxidant activities.
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Nitecapone : A NITRIC OXIDE RADICAL SCAVENGER
Biochemistry and molecular biology international, 1994Co-Authors: Lucia Marcocci, John J. Maguire, Lester PackerAbstract:Nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], is a scavenger of nitric oxide produced in vitro. It reduced the rate of methemoglobin formation from oxyhemoglobin exposed to nitric oxide generated from the reaction of hydroxylamine with Complex I of catalase and it decreased the amount of nitrite formed in the reaction of oxygen with nitric oxide generated from sodium nitroprusside. Nitecapone also affected the L-arginine dependent accumulation of nitrite in a suspension of peritoneal rat neutrophils. The related compounds entacapone [2-cyano-N, N-diethyl-3-(3,4 dihydroxy-5-nitrobenzyl)-propenamide] and OR 1246 [3-(3,4-dihydroxy-5-nitrobenzyl)-2,4-pentanedione] were also able to scavenge nitric oxide. The action of Nitecapone on nitric oxide expands the role of Nitecapone as a scavenger of reactive oxygen species, and suggests Nitecapone, entacapone and OR 1246 as potential therapeutic agents for the treatment of diseases connected with increased production of nitric oxide.
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Nitecapone protects the Langendorff perfused heart against ischemia-reperfusion injury.
Biochemistry and molecular biology international, 1993Co-Authors: M. Valenza, Lester Packer, Elena Serbinova, S Khwaja, Judith D. CatudiocAbstract:We assessed the protection afforded against myocardial ischemia/reperfusion by Nitecapone in the Langendorff heart model using male Sprague-Dawley rats. We found that when present in the perfusate 10 microM Nitecapone improved the mechanical function of the heart and lowered the enzyme leakage of lactate dehydrogenase after 40 minutes of global ischemia. In Nitecapone treated hearts the content of oxidized proteins and lipids (carbonyl groups and endogenous lipid fluorescent products) decreased. Nitecapone partially prevented the loss of total sulfhydryl groups and vitamin E after ischemia and reperfusion. We suggest that the mechanism of Nitecapone protection most likely involves direct antioxidant action and enhancing the activity of other antioxidants.
Eivor Elovaara - One of the best experts on this subject based on the ideXlab platform.
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Characterization of catechol glucuronidation in rat liver.
Drug Metabolism and Disposition, 2002Co-Authors: Laurence Antonio, Joël-paul Grillasca, Brian Burchell, Marie-helene Piet, Brian T. Ethell, Mohamed Ouzzine, Sylvie Fournel-gigleux, Jyrki Taskinen, Eivor Elovaara, Jacques MagdalouAbstract:Catechols are a class of substances from natural or synthetic origin that contain a 1,2-dihydroxybenzene group. We have characterized the glucuronidation by rat liver microsomes and by the rat liver recombinant UDP-glucuronosyltransferase isoforms UGT1A6 and UGT2B1 of a series of 42 structurally diverse catechols, including neurotransmitters, polyphenols, drugs, and catechol estrogens. Small catechols (4-nitrocatechol, 2,3-dihydroxybenzaldehyde, 4-methylcatechol, and tetrachlorocatechol), tyrphostine A23, and octylgallate were glucuronidated at the highest rate by rat liver microsomes and the recombinant enzymes. By contrast, polyphenols from green tea (catechin and related compounds), 3,5-dinitrocatechol, the catechol- O -methyltransferase inhibitor drugs (entacapone, Nitecapone, and tolcapone), the carboxyl catechols (gallic acid and dihydroxybenzoic acid derivatives), and the neurotransmitters and dopaminergic drugs, except dobutamine, were glucuronidated at low rate. Glucuronidation of most catechols was increased upon treatment of rats by 3-methylcholanthrene (3-MC) or Aroclor 1254. No induction was observed after administration of phenobarbital and clofibrate or treatment with catechols. Partial least-squares modeling was carried out to explain the variations of glucuronidation activity by liver microsomes of nontreated and 3-MC-treated rats. The model developed explained 82% and predicted 61% of the variations of glucuronidation activities. Among the 17 electronic and substructure parameters used that characterize the catechols, the hydrophobicity/molar volume ratio of catechols showed a strong positive correlation with the glucuronidation rate. The effect of the p K aof the catechol group was modeled to be nonlinear, the optimal p K a value for glucuronidation being between 8 and 9. Hydrogen bonding and steric effects also were important to account for to predict the glucuronidation rates.
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Enzyme-assisted synthesis and structural characterization of nitrocatechol glucuronides.
Bioconjugate chemistry, 1999Co-Authors: Leena Luukkanen, Eivor Elovaara, Pekka Ottoila, Ilkka Kilpeläinen, Heli Kangas, Jyrki TaskinenAbstract:Enzyme-assisted synthesis and characterization are described for 3-O-β-d-glucuronides 1b−4b of the aglycons E- and Z-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide (entacapone), 1a and 2a, respectively, 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione (Nitecapone) 3a and 4‘-methyl-3,4-dihydroxy-5-nitrobenzophenone (tolcapone) 4a, and 1-o- and 2-o-glucuronides 5b and 6b of the aglycon 1,2-dihydroxy-4-nitrobenzene 5a. Liver microsomes from rats pretreated with Aroclor 1254 were used as catalyst in the synthesis. Glucuronidation was regio- and stereoselective in the case of 1a−4a; only one product was observed by HPLC, HPTLC, and NMR. The glucuronidation of 1,2-dihydroxy-4-nitrobenzene 5a resulted in equal amounts of 1-O-β-d- and 2-O-β-d-glucuronides. Purification of the crude products by C18 solid-phase extraction and/or flash chromatography gave compounds 1b−6b in 38−98% yields (50−84 mg). The structures of the glucuronides were characterized on the basis of UV and IR spectra and confi...
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Glucuronidation of Entacapone, Nitecapone, Tolcapone, and Some Other Nitrocatechols by Rat Liver Microsomes
Pharmaceutical Research, 1997Co-Authors: Pia Lautala, Eivor Elovaara, Maija Kivimaa, Hannele Salomies, Jyrki TaskinenAbstract:Purpose . Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds. Methods . The glucuronidation kinetics of seven nitrocatechols and 4-nitrophenol, the reference substrate for phenol UDP-glucuronosyltrans-ferase activity, was measured in liver microsomes from creosote-treated rats and determined by non-linear fitting of the experimental data to the Michaelis-Menten equation. A new method that combined densitometric and radioactivity measurement of the glucuronides separated by HPTLC was developed for the quantification. Results . Apparent K_m values for the nitrocatechols varied greatly depending on substitution pattern being comparable with 4-nitrophenol (0.11 mM) only in the case of 4-nitrocatechol (0.19 mM). Simple nitrocatechols showed two-fold V_max values compared with 4-nitrophenol (68.6 nmol min^−1 mg^−1), while all disubstituted catechols exhibited much lower glucuronidation rate. V_max/K_m values were about 10 times higher for monosubstituted catechols compared to disubstituted ones. The kinetic parameters for COMT inhibitors were in the following order: K_m Nitecapone >> entacapone > tolcapone; V_max Nitecapone > entacapone > tolcapone; V_max/K_m tolcapone > Nitecapone > entacapone. Conclusions . Nitrocatechols can in principle be good substrates of UGTs. However, substituents may have a remarkable effect on the enzyme kinetic parameters. The different behaviour of Nitecapone compared to the other COMT inhibitors may be due to its hydrophilic 5-substituent. The longer elimination half-life of tolcapone in vivo compared to entacapone could not be explained by glucuronidation kinetics in vitro .
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glucuronidation of entacapone Nitecapone tolcapone and some other nitrocatechols by rat liver microsomes
Pharmaceutical Research, 1997Co-Authors: Pia Lautala, Eivor Elovaara, Maija Kivimaa, Hannele Salomies, Jyrki TaskinenAbstract:Purpose. Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds.
Pekka T. Männistö - One of the best experts on this subject based on the ideXlab platform.
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Nitecapone reduces development and symptoms of neuropathic pain after spinal nerve ligation in rats.
European journal of pain (London England), 2011Co-Authors: Oleg Kambur, Pekka T. Männistö, Anne M. Pusa, Mikko Käenmäki, Eija Kalso, Vesa K. KontinenAbstract:Neuropathic pain is caused by damage or malfunctioning of the nervous system. It is fairly common and more resistant to treatment than other types of pain. Since Nitecapone, an inhibitor of catechol-O-methyl-transferase (COMT), has decreased neuropathic symptoms in diabetic rats, we studied its effects in another model of neuropathic pain, the spinal nerve ligation (SNL) model. Spinal nerves L5-6 were ligated in male Wistar rats under anaesthesia to produce the SNL model of neuropathic pain. Nitecapone (30 mg/kg, i.p.) or vehicle was administered once daily starting either 1h before or 2 days after surgery and continued for 14-19 days. Threshold for mechanical allodynia was measured with the digital von Frey test and responses to cold stimuli with the acetone test, before surgery and every other day after it 1h before drug administration. Mechanical and cold allodynia developed in all study groups. Both Nitecapone treatments significantly reduced mechanical allodynia and withdrawal thresholds were 80-95% higher compared with the control group. In the acetone test, both Nitecapone groups also showed less signs of cold allodynia than the control groups. In Nitecapone-naive animals a single dose of Nitecapone also reduced mechanical allodynia on the 14th day after the surgery. Nitecapone reduced the symptoms of neuropathic pain after the SNL, which is in line with the earlier study. Our results suggest that Nitecapone and other COMT inhibitors should be studied further in the treatment of neuropathic pain.
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Inhibitors of catechol-O-methyltransferase sensitize mice to pain.
British journal of pharmacology, 2010Co-Authors: Oleg Kambur, Eija Kalso, Vesa K. Kontinen, Antti Pertovaara, R Talka, O.b. Ansah, Pekka T. MännistöAbstract:BACKGROUND AND PURPOSE Catechol-O-methyltransferase (COMT) inhibitors are used in Parkinson's disease in which pain is an important symptom. COMT polymorphisms modulate pain and opioid analgesia in humans. In rats, COMT inhibitors have been shown to be pro-nociceptive in acute pain models, but also to attenuate allodynia and hyperalgesia in a model of diabetic neuropathy. Here, we have assessed the effects of acute and repeated administrations of COMT inhibitors on mechanical, thermal and carrageenan-induced nociception in male mice. EXPERIMENTAL APPROACH We used single and repeated administration of a peripherally restricted, short-acting (Nitecapone) and also a centrally acting (3,5-dinitrocatechol, OR-486) COMT inhibitor. We also tested CGP 28014, an indirect inhibitor of COMT enzyme. Effects of OR-486 on thermal nociception were also studied in COMT deficient mice. Effects on spinal pathways were assessed in rats given intrathecal Nitecapone. KEY RESULTS After single administration, both Nitecapone and OR-486 reduced mechanical nociceptive thresholds and thermal nociceptive latencies (hot plate test) at 2 and 3 h, regardless of their brain penetration. These effects were still present after chronic treatment with COMT inhibitors for 5 days. Intraplantar injection of carrageenan reduced nociceptive latencies and both COMT inhibitors potentiated this reduction without modifying inflammation. CGP 28014 shortened paw flick latencies. OR-486 did not modify hot plate times in Comt gene deficient mice. Intrathecal Nitecapone modified neither thermal nor mechanical nociception. CONCLUSIONS AND IMPLICATIONS Pro-nociceptive effects of COMT inhibitors were confirmed. The pro-nociceptive effects were primarily mediated via mechanisms acting outside the brain and spinal cord. COMT protein was required for these actions.
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Catechol-O-methyltransferase and pain.
International review of neurobiology, 2010Co-Authors: Oleg Kambur, Pekka T. MännistöAbstract:In animals, different types of COMT inhibitors, irrespective of their brain penetration, are pro-nociceptive in several models of acute and inflammatory pain. Similarly, COMT knock-out mice are more sensitive to nociceptive stimuli, whereas in mice over-expressing a high activity COMT variant nociceptive sensitivity is decreased. COMT knock-out mice also show altered response to opioids and stress-induced analgesia. In different rat models of neuropathic pain, the action of Nitecapone is opposite: it is antinociceptive and antiallodynic. Complex actions of low COMT activity may be caused by enhanced adrenergic and dopaminergic activities that play different and even contrasting roles at different parts of the nociceptive system. Also compensatory changes in other neurotransmitters may occur. Pro-nociceptive effects seem to be caused by increased activation of peripheral adrenergic β(2)- and β(3) -receptors. Other properties of COMT inhibitors, like scavenging of oxygen and nitrogen radicals, may be important in antiallodynic effects found in neuropathic pain models. Increased number of µ-opioid receptors in certain brain areas may be responsible of enhanced opioid effects associated with a low COMT activity. In human pain studies, a low COMT activity is often associated with increased pain sensitivity in experimental pain models and with increased pre- and postoperative pain in acute clinical situations. As a rule, a simultaneous occurrence of several SNPs within the haplotype, causing low COMT activity, is more often associated with pain than any single SNP alone. In experimental pain studies, all negative findings resulted from concentrating solely on SNP rs4680 (Val158Met). Virtually all studies assessing haplotypes were able to confirm an association of a low COMT and increased pain. In chronic clinical pain, the effect of COMT polymorphisms depends on the pain conditions. Hence, in neuropathic and cancer pains, COMT activity is meaningless but in some chronic musculoskeletal pain conditions and migraine or headache low COMT activity appears to increase incidence and symptoms. A low COMT activity also increases availability of opioid receptors and may enhance opioid analgesia and adverse effects at least in cancer pains.
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General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase.
General pharmacology, 1994Co-Authors: Seppo Kaakkola, Ariel Gordin, Pekka T. MännistöAbstract:1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, Nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and Nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, Nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.
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Effect of Nitecapone and clorgyline, given intracerebro-ventricularly on L-dopa metabolism in the rat brain.
Neuroreport, 1992Co-Authors: Pekka T. Männistö, M. Törnwall, P. Tuomainen, S. A. Borisenko, Raimo K. TuominenAbstract:A new COMT inhibitor, Nitecapone (OR-462) or clorgyline, a MAO-A inhibitor, was infused into the 3rd brain ventricle (i.c.v.) of conscious male rats. None of the enzyme inhibitors given alone alter hypothalamic or striatal levels of L-dopa, dopamine or their metabolites. Most of the rats were pretreated with levodopa/carbidopa (LD/CD, 15/30 mg kg-1 intraperitoneally). Now, the action of Nitecapone is localized in the hypothalamus since homovanillic acid (HVA) is decreased there, not in the striatum. The levels of 3-O-methyldopa (3-OMD) are not changed in either brain region, suggesting a lack of the peripheral leakage of Nitecapone. Clorgyline (3 and 10 micrograms rat-1) elevates hypothalamic and dopamine levels. Nitecapone and clorgyline decrease prolactin (PRL) levels below those reduced by LD/CD treatment.
Anita Aperia - One of the best experts on this subject based on the ideXlab platform.
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role of oxidative stress in advanced glycation end product induced mesangial cell activation
Kidney International, 2002Co-Authors: Hjalmar Brismar, Annchristine Eklof, Anita AperiaAbstract:Role of oxidative stress in advanced glycation end product-induced mesangial cell activation . Background Levels of advanced glycation end products (AGE) are elevated in individuals with advancing age, renal failure, and diabetes, and accumulation of these molecules may contribute to disease progression. The mechanism by which AGE proteins alter glomerular mesangial cell function, however, is not completely understood. The present study assessed the involvement of oxidative stress in AGE-dependent mesangial cell signaling events. Methods Primary cultures of rat renal mesangial cells were exposed to in vitro AGE-BSA and H 2 O 2 . Nuclear factor-κB (NF-κB) and protein kinase C (PKC) isoform activation were studied using confocal microscopy and Western blotting. Quantitative polymerase chain reaction (PCR) was used to measure transforming growth factor-β1 (TGF-β1) levels. The involvement of oxidative stress was assessed by supplementing or compromising cellular antioxidant capacity. Results NF-κB was dose-dependently activated by AGE. PKC activation was not involved in this response, but analysis of PKC-β1 activation showed a stimulatory effect of AGE proteins on this isoform. Transcription of TGF-β1 was stimulated by AGE and was prevented by PKC inhibition. Challenge with H 2 O 2 had similar downstream effects on mesangial cell signaling. Antioxidants, vitamin E and Nitecapone, prevented AGE-dependent NF-κB activation and normalized PKC activity and associated TGF-β1 transcription. Depletion of the intracellular antioxidant, glutathione, effectively lowered the AGE concentration needed for mesangial cell activation of NF-κB and PKC-β1. Treatment with a suboptimal AGE dose, under glutathione-depleted conditions, revealed a synergistic effect on both parameters. Conclusion The results support a central role for oxidative stress in AGE-dependent mesangial cell signaling and emphasize the importance of ROS in determining cell responsiveness.
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Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats
Diabetes, 2000Co-Authors: M. A. Lal, Annchristine Eklof, Anna Körner, Y. Matsuo, S. Zelenin, Sam X. Cheng, G. Jaremko, G. F. Dibona, Anita AperiaAbstract:The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of Nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of Nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by Nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by Nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of Nitecapone provide a protective therapy against the development of diabetic nephropathy.
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Combined Antioxidant and COMT Inhibitor Treatment Reverses Renal Abnormalities in Diabetic Rats
2000Co-Authors: M. A. Lal, Annchristine Eklof, Anna Körner, Y. Matsuo, S. Zelenin, Sam X. Cheng, G. Jaremko, G. F. Dibona, Anita AperiaAbstract:The development and progression of diabetic nephropa-thy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of Nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nite-capone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by Nitecapone, but in a manner that is more readily attributed to the antioxi-dant potential of the agent. A pattern of elevated oxida
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Inhibition of COMT induces dopamine-dependent natriuresis and inhibition of proximal tubular Na+,K+-ATPase
Kidney international, 1997Co-Authors: Annchristine Eklof, Ulla Holtbäck, Martin Sundelöf, Shanlin Chen, Anita AperiaAbstract:Inhibition of COMT induces dopamine-dependent natriuresis and inhibition of proximal tubular Na + ,K + -ATPase. The enzyme catechol-O-methyltransferase (COMT), which plays an important role for dopamine metabolism, is abundantly expressed in the kidney. To test whether the natriuretic effects of dopamine may be related to the rate of dopamine metabolism, rats were treated with Nitecapone, a peripheral inhibitor of COMT. Nitecapone, given by gavage, induced a highly significant (5.6-fold) increase in sodium excretion, which was associated with an inhibition of the Na + ,K + -ATPase activity in both the proximal convoluted and proximal straight tubules (PCT and PST, respectively). These effects were completely abolished if the rats were also treated with a specific dopamine 1 antagonist, SCH 23390. Furthermore, the natriuretic effect of Nitecapone was also observed in rats on a high salt diet. The kidney-specific pro-drug to dopamine, glu-dopa, induced a significant, but less pronounced increase in urinary sodium excretion, associated with a dopamine-dependent inhibition of the Na + ,K + -ATPase activity in the PCT but not in the PST. Nitecapone and glu-dopa had an additive natriuretic effect. It is concluded that COMT plays an important role in determining the natriuretic effects of the renal dopamine system.